Substituted N-aryl heterocycles, process for their preparation and their use as medicaments

ABSTRACT

The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof. 
     Compounds of the formula I 
                         
in which the radicals have the stated meanings, the N-oxides and the physiologically tolerated salts thereof and process for the preparation thereof are described. The compounds are suitable for example as anorectic agents.

This application claims priority from Provisional Application 60/488,545 filed Jul. 18, 2003.

The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof.

Compounds having a pharmacological effect and similar in their overall structure to the N-aryl heterocycles described herein have already been described in the prior art. Thus, for example, WO 00/35454 describes ureido-substituted phenylpiperidines and -pyrrolidines as agents for the treatment of inflammatory and autoimmune diseases. Acylamido-substituted phenylpyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and disorders of lipid metabolism.

The invention was based on the object of providing compounds which bring about a weight reduction in mammals and are suitable for preventing and treating obesity and diabetes.

The invention therefore relates to compounds of the formula I

wherein

-   R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CR78R79)_(o)-R12,     (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, aryloxy-(C₁-C₄)-alkyl,     (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl,     —CO—(CH₂)_(o)-R12, CO-aryloxy-(C₁-C₄)-alkyl, CO—(C₂-C₈)-alkenyl,     CO—(C₂-C₈)-alkynyl, COCH═CH(R13), COCC(R14), CO—(C₁-C₄)     -alkyl-S(O)_(p)-(C₁-C₄)-alkyl, CO(C(R15)(R16))_(q)N(R17)(R18),     CO(C(R19)(R20))_(r)CON(R21)(R22) or CO(C(R23)(R24))_(s)O(R25); or     -   R1 and R2, together with the nitrogen atom to which they are         attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-,         bi- or spirocyclic ring which, apart from said nitrogen atom of         attachment, optionally contains 1, 2, 3 or 4 additional         heteroatoms selected from the group of oxygen, nitrogen and         sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂,         CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,         (C₀-C₈)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,         COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃;     -   wherein         -   o is 0, 1, 2, 3, 4, 5 or 6;         -   p is 0, 1 or 2         -   q, r, s are each independently 0, 1, 2, 3 or 4;         -   R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or             10-membered aromatic ring system optionally containing 1 or             2 heteroatoms selected from the group of nitrogen, oxygen             and sulfur, and is optionally substituted by F, Cl, Br, CF₃,             NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;         -   R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27,             R28, R29, R30, R31, R32 are each independently H or             (C₁-C₆)-alkyl;         -   R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or         -   substituent pairs R17 and R18, R21 and R22, R27 and R28, and             R31 and R32, independently of one another and taken together             with the nitrogen atom to which they are attached,             optionally form a 5- or 6-membered ring which, apart from             said nitrogen atom of attachment, optionally contains one             additional heteroatom component selected from the group of             N—(C₁-C₆)-alkyl, oxygen and sulfur;         -   R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring             system which optionally contains 1 or 2 heteroatoms selected             from the group of nitrogen, oxygen and sulfur, and is             optionally substituted by F, Cl, Br, CF₃, NO₂, CN,             (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;         -   R12 is OH, O—(C₁-C₆)-alkyl, O(C₀-C₈)-alkylene-aryl, CN,             S—(C₁-C₆)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83) or a             3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered mono-,             bi- or spirocyclic ring which optionally contains one or             more heteroatoms selected from the group of N, O and S, and             is optionally substituted with F, Cl, Br, I, OH, CF₃, NO₂,             CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,             (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,             (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,             O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl,             O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,             O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36),             (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39),             CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u)(R41)             or COOH;         -   t is 0, 1, 2, 3, 4, 5 or 6;         -   u is 0, 1 or 2;     -   R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl; or     -   R34 and R35, taken together with the nitrogen atom to which they         are attached, optionally form a 5- or 6-membered ring which,         apart from said nitrogen atom of attachment, optionally contains         one additional heteroatom component selected from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally         substituted by 1 or 2 oxo groups;     -   R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-,         7-, 8-, 9- or 10-membered aromatic ring system wherein said         aromatic ring system optionally contains one or two additional         heteroatoms selected from the group of nitrogen, oxygen and         sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂,         CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;     -   R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or         (C₀-C₈)-alkylene-aryl;     -   R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered         aromatic ring system optionally containing one or two         heteroatoms from the group of nitrogen, oxygen and sulfur, and         optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl         or O—(C₁-C₈)-alkyl;     -   R78, R79 are each independently H, (C₁-C₈)-alkyl,         hydroxy-(C₁-C₄)-alkyl, OH or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;     -   R80, R81, R93 are each independently (C₁-C₈)-alkyl,         (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl;     -   R82, R83 are each independently H or (C₁-C₆)-alkyl; or     -   R82 and R83, taken together with the nitrogen atom to which they         are attached, optionally form a 5- or 6-membered ring which,         apart from said nitrogen atom of attachment, optionally contains         one additional heteroatom component selected from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally         substituted by 1 or 2 oxo groups; -   R3 is H or (C₁-C₆)-alkyl; -   R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl,     O—CO(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; -   R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl; or     -   substituent pairs R6 and R7, and R8 and R9, optionally form,         independently of one another, an oxo group; -   n, m are each independently 0, 1 or 2; -   A, B, D, G are each independently N or C(R42); or     -   said radicals A and B, or said radicals D and G are each C(R42)         and, taken together, optionally form a 5- or 6 membered         carbocyclic or heterocyclic radical resulting in an overall         bicyclic ring system;     -   wherein         -   R42 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,             O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,             S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,             (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,             (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,             (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,             O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R43)(R44), SO₂—CH₃, COOH,             COO—(C₁-C₆)-alkyl, CON(R45)(R46), N(R47)CO(R48),             N(R49)SO₂(R50), CO(R51) or —(CR84R85)_(x)—O(R86);             -   wherein             -   R43, R44, R45, R46, R47, R49 are each independently H or                 (C₁-C₈)-alkyl; or             -   substituent pairs R43 and R44, and R45 and R46,                 independently of one another and taken together with the                 nitrogen atom to which they are attached, optionally                 form a 5- or 6-membered ring which, apart from said                 nitrogen atom of attachment, optionally contains an                 additional heteroatom component selected from the group                 of N—(C₁-C₆)-alkyl, oxygen and sulfur;             -   R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or                 aryl;             -   R84, R85 are each independently H or (C₁-C₈)-alkyl;             -   R86 is H, (C₁-C₆)-alkyl or aryl;             -   x is 1, 2, 3, 4, 5 or 6; -   R10 is H, (C₁-C₈)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-alkynyl; -   X is N(R52), O, a bond, C═C, C(R53)(R54), C(R55)(R56)O, CO, C≡C, or     a group of the formula —(CR87R88)_(Y)-wherein one or more     —(CR87R88)-units contained in said group of formula —(CR87R88)_(Y)—     is optionally replaced by Y;     -   wherein         -   Y is O, S or N(R89) wherein R89 is H or (C₁-C₈)-alkyl;         -   R52, R53, R54, R55, R56 are each independently H or             (C₁-C₈)-alkyl;         -   R87, R88 are each independently H or (C₁-C₄)-alkyl, and may             be defined the same or differently in each of said             —(CR87R88)-units contained in said group of formula             —(CR87R88)_(Y)-;         -   y is 2, 3, 4, 5 or 6; -   E is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13- or 14-membered bivalent     carbo- or heterocyclic ring structure with 0, 1, 2, 3 or 4     heteroatoms selected from the group of N, O and S, and optionally     substituted with H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, oxo,     O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,     (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,     O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,     (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl,     S-aryl, N(R57)(R58), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,     CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65), and wherein     said bivalent carbo- or heterocyclic ring structure is mono- or     bicyclic;     -   wherein         -   R57, R58, R59, R60, R61, R63 are each independently H or             (C₁-C₈)-alkyl; or         -   substituent pairs R57 and R58, and R59 and R60,             independently of one another and taken together with the             nitrogen atom to which they are attached, optionally form a             5- or 6-membered ring which, apart from said nitrogen atom             of attachment, optionally contains one further heteroatom             component selected from the group of N—(C₁-C₆)-alkyl, oxygen             and sulfur;         -   R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or             aryl; -   K is a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68),     (C(R69)(R70))_(v), CO, C≡C, C═C or a group of the formula     —(CR90R91)_(Z)-in which one or more of the —(CR90R91)-units     contained in said group of the formula —(CR90R91)_(Z)-is optionally     replaced by Z;     -   wherein         -   v is 1, 2, 3 or 4         -   R66, R67, R68, R69, R70 are each independently H or             (C₁-C₈)-alkyl;         -   Z is O, S, N(R92), CO, SO or SO₂;         -   R90, R91 are each independently H, (C₁-C₈)-alkyl,             hydroxy-(C₁-C₄)-alkyl, hydroxy or             (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, and wherein R90 and R91 may be             defined the same or differently in each of said             —(CR90R91)-units contained in said group of formula             —(CR90R91)_(Z)-;         -   z is 2, 3, 4, 5 or 6;         -   R92 is H or (C₁-C₈)-alkyl; -   R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or     10-membered mono-, bi- or spirocyclic ring, optionally containing 1,     2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen     and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN,     (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy,     hydroxy-(C₁-C₄)-alkyl, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77),     SO₂CH₃ or SCF₃;     -   wherein         -   R71, R72, R73, R74, R75, R76, R77 are each independently H             or (C₁-C₈)-alkyl; or         -   substituent pairs R72 and R73, and R76 and R77,             independently of one another and taken together with the             nitrogen atom to which they are attached, optionally form a             5- or 6-membered ring which, apart from the nitrogen atom,             optionally contain one additional heteroatom component             selected from the group of N—(C₁-C₆)-alkyl, oxygen and             sulfur; or -   E, K and R11 taken together form a tricyclic system where each of     the rings in said tricyclic system are, independently of one     another, saturated, partially saturated or unsaturated, and wherein     each ring is comprised of 3-8 ring atoms; -   and the N-oxides and pharmaceutically acceptable salts thereof.

In a further embodiment, the invention therefore relates to compounds of the formula I in which the meanings are:

wherein

-   R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CR78R79)_(o)-R12,     (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, aryloxy-(C₁-C₄)-alkyl,     (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl,     —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl, CO—(C₂-C₈)-alkenyl,     CO—(C₂-C₈)-alkynyl, COCH═CH(R13), COCC(R14),     CO—(C₁-C₄)-alkyl-S(O)_(p)—(C₁-C_(CO(C(R)15)(R16))_(q)N(R17)(R18),     CO(C(R19)(R20))_(r)CON(R21 )(R22) or CO(C(R23)(R24))_(s)O(R25); or     -   R1 and R2, together with the nitrogen atom to which they are         attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-,         bi- or spirocyclic ring which, apart from said nitrogen atom of         attachment, optionally contains 1, 2, 3 or 4 additional         heteroatoms selected from the group of oxygen, nitrogen and         sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂,         CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo,         CO(R26), CON(R27)(R28), hydroxy, COO(R29),         N(R30)CO(C₁-C₆)-alkyl, N(R31 )(R32) or SO₂CH₃;     -   wherein         -   o is, 0, 1, 2, 3, 4, 5 or 6;         -   p is 0, 1 or 2         -   q, r, s are each independently 0, 1, 2, 3 or 4;         -   R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or             10-membered aromatic ring system optionally containing 1 or             2 heteroatoms selected from the group of nitrogen, oxygen             and sulfur, and is optionally substituted by F, Cl, Br, CF₃,             NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;         -   R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27,             R28, R29, R30, R31, R32 are each independently H or             (C₁-C₆)-alkyl;         -   R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or         -   substituent pairs R17 and R18, R21 and R22, R27 and R28, and             R31 and R32, independently of one another and taken together             with the nitrogen atom to which they are attached,             optionally form a 5- or 6-membered ring which, apart from             said nitrogen atom of attachment, optionally contains one             additional heteroatom component selected from the group of             N—(C₁-C₆)-alkyl, oxygen and sulfur;         -   R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring             system which optionally contains 1 or 2 heteroatoms selected             from the group of nitrogen, oxygen and sulfur, and is             optionally substituted by F, Cl, Br, CF₃, NO₂, CN,             (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;         -   R12 is OH or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or             12-membered mono-, bi- or spirocyclic ring which optionally             contains one or more heteroatoms selected from the group of             N, O and S, and is optionally substituted with F, Cl, Br, I,             OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,             (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,             (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,             O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl,             O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,             O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36),             (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39),             CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u)(R41)             or COOH;         -   t is 0, 1, 2, 3, 4, 5 or 6;         -   u is 0, 1 or 2;     -   R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl; or     -   R34 and R35, taken together with the nitrogen atom to which they         are attached, optionally form a 5- or 6-membered ring which,         apart from said nitrogen atom of attachment, optionally contains         one additional heteroatom component selected from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally         substituted by 1 or 2 oxo groups;     -   R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-,         7-, 8-, 9- or 10-membered aromatic ring system wherein said         aromatic ring system optionally contains one or two additional         heteroatoms selected from the group of nitrogen, oxygen and         sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂,         CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;     -   R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or         (C₀-C₈)-alkylene-aryl;     -   R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered         aromatic ring system optionally containing one or two         heteroatoms from the group of nitrogen, oxygen and sulfur, and         optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl         or O—(C₁-C₈)-alkyl; -   R3 is H or (C₁-C₆)-alkyl; -   R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl,     O—CO(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; -   R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl; or     -   substituent pairs R6 and R7, and R8 and R9, optionally form,         independently of one another, an oxo group; -   n, m are each independently 0, 1 or 2; -   A, B, D, G are each independently N or C(R42);     -   wherein     -   R42 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,         O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,         (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,         (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,         (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl,         N(R43)(R44), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R45)(R46),         N(R47)CO(R48), N(R49)SO₂(R50) or CO(R51);         -   wherein         -   R43, R44, R45, R46, R47, R49 are each independently H or             (C₁-C₈)-alkyl; or         -   substituent pairs R43 and R44, and R45 and R46,             independently of one another and taken together with the             nitrogen atom to which they are attached, optionally form a             5- or 6-membered ring which, apart from said nitrogen atom             of attachment, optionally contains an additional heteroatom             component selected from the group of N—(C₁-C₆)-alkyl, oxygen             and sulfur;         -   R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or             aryl; -   R10 is H, (C₁-C₈)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-alkynyl; -   X is N(R52), O, a bond, C═C, C(R53)(R54) or C(R55)(R56)O;     -   wherein         -   R52, R53, R54, R55, R56 are each independently H or             (C₁-C₈)-alkyl; -   E is a 3, 4, 5, 6, 7 or 8-membered bivalent carbo- or heterocyclic     ring structure with 0, 1, 2, 3 or 4 heteroatoms selected from the     group of N, O and S, and optionally substituted with H, F, Cl, Br,     I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,     O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,     (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,     (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,     (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58),     SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R59)(R60), N(R61)CO(R62),     N(R63)SO₂(R64) or CO(R65), and wherein said bivalent carbo- or     heterocyclic ring structure is mono- or bicyclic;     -   wherein         -   R57, R58, R59, R60, R61, R63 are each independently H or             (C₁-C₈)-alkyl; or         -   substituent pairs R57 and R58, and R59 and R60,             independently of one another and taken together with the             nitrogen atom to which they are attached, optionally form a             5- or 6-membered ring which, apart from said nitrogen atom             of attachment, optionally contains one further heteroatom             component selected from the group of N—(C₁-C₆)-alkyl, oxygen             and sulfur;         -   R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or             aryl; -   K is a bond, O, OCH₂, CH₂O, S, SO, SO2, N(R66), N(R67)CO, CON(R68),     (C(R69)(R70))v, CO or C≡C;     -   wherein         -   v is 1, 2, 3 or 4         -   R66, R67, R68, R69, R70 are each independently H or             (C₁-C₈)-alkyl; -   R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or     10-membered mono-, bi- or spirocyclic ring, optionally containing 1,     2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen     and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN,     (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy,     COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃;     -   wherein         -   R71, R72, R73, R74, R75, R76, R77 are each independently H             or (C₁-C₈)-alkyl; or         -   substituent pairs R72 and R73, and R76 and R77,             independently of one another and taken together with the             nitrogen atom to which they are attached, optionally form a             5- or 6-membered ring which, apart from the nitrogen atom,             optionally contain one additional heteroatom component             selected from the group of N—(C₁-C₆)-alkyl, oxygen and             sulfur; or -   E, K and R11 taken together form a tricyclic system where each of     the rings in said tricyclic system are, independently of one     another, saturated, partially saturated or unsaturated, and wherein     each ring is comprised of 3-8 ring atoms;     and the N-oxides and pharmaceutically acceptable salts thereof.

The invention relates to compounds of the formula I in the form of their racemates, enantiomer-enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92 and R93 may be either straight-chain, branched or optionally halogenated.

The term “aryl” means in particular a phenyl or naphthyl group.

A “tricyclic system” means structures having 3 rings which are connected together by more than one bond. Examples of such systems are fused systems with 3 rings and spirocycles with a ring system fused on.

In the case where R1 and R2 form together with the nitrogen atom to which they are bonded a ring, this ring may be substituted by one or more of the substituents mentioned.

The bivalent carbo- or heterocyclic ring structure E includes structures which are linked by one and the same atom to the two adjacent groups K and X.

Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid. For medical purposes the chlorine salt is particularly preferably used. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts).

Salts with a pharmaceutically unacceptable anion likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula (I)” hereinafter refer to compound(s) of the formula (I) as described above, and their salts, solvates and physiologically functional derivatives as described herein.

If radicals or substituents can occur more than once in the compounds of the formula I, they may all have independently of one another the stated meanings and be identical or different.

In a particularly preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are:

-   R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CH₂)_(o)—R12,     (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,     COCH═CH(R13), COCC(R14), CO—(C₁-C₄)-alkyl-S(O)_(p)—(C₁-C₄)-alkyl,     CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(r)CON(R21)(R22) or     CO(C(R23)(R24))_(s)O(R25); or R1 and R2 together with the nitrogen     atom to which they are attached, optionally form a 4-, 5-, 6-, 7,     8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart     from he nitrogen atom, may comprise 0 to 2 additional heteroatoms     selected from the group of oxygen, nitrogen and sulfur, where the     heterocyclic ring system may additionally be substituted by F,     (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R26),     CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32)     or SO₂CH₃, where R1 and R2 are preferably not both H, and R1 and R2     together with the nitrogen atom are preferably not a morpholino     radical; -   o 0, 1, 2, 3, 4; -   p 0, 1, 2; -   q, r, s independently of one another 0, 1, 2, 3, preferably q, s are     independently of one another 1, 2, 3 and r is 0, 1, 2, 3; -   R13, R14 independently of one another a 5-10 membered aromatic ring     system which may comprise a further heteroatom from the group of     nitrogen, oxygen and sulfur and may be substituted by F, Cl,     (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl;     -   R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28,         R29, R30, R31, R32     -   independently of one another H, (C₁-C₆)-alkyl; -   R18 H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl, CO(R33); -   R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of     one another optionally together with the nitrogen atom to which they     are bonded a 5-6 membered ring which, apart from the nitrogen atom,     may also comprise 0-1 further heteroatoms from the group of     N—(C₁-C₆)-alkyl, oxygen and sulfur; -   R33 a 5-10 membered aromatic ring system which may comprise a     further heteroatom from the group of nitrogen, oxygen and sulfur and     may be substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may     comprise one or more heteroatoms from the group of N, O and S, and     the 3-12 membered ring may comprise further substituents such as F,     Cl, CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,     O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36),     (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t) (R39), CO(C₁-C₆)-alkyl,     COCOO(C₁-C₆)-alkyl, COO(R40) and S(O)_(u) (R41), where in a     preferred embodiment the substituent O—(C₁-C₆)-alkyl is excluded     when the 3-12 membered ring is phenyl; -   t 0, 1, 2, 3, 4; -   u 0, 1, 2; -   R34, R35, R37, R38     -   independently of one another H, (C₁-C₈)-alkyl; -   R34 and R35     -   optionally together with the nitrogen atom to which they are         bonded a 5-6 membered ring which, apart from the nitrogen atom,         may also comprise 0-1 further heteroatoms from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur and may optionally be         substituted by 1-2 oxo groups; -   R36, R39 independently of one another (C₃-C₈)-cycloalkyl, 5-10     membered aromatic ring system which may comprise a further     heteroatom from the group of nitrogen, oxygen and sulfur and may be     substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R40 H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl, (C₀-C₈)-alkylene-aryl; -   R41 (C₁-C₆)-alkyl, 5-10 membered aromatic ring system which may     comprise 0-2 further heteroatoms from the group of nitrogen, oxygen     and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl,     O—(C₁-C₈)-alkyl; -   R3 H, (C₁-C₆)-alkyl; -   R4, R5 independently of one another H, (C₁-C₆)-alkyl, OH,     O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl; -   R6, R7, R8, R9     -   independently of one another H, (C₁-C₈)-Alkyl; -   R6 and R7, R8 and R9     -   independently of one another optionally oxo; -   n, m independently of one another 0, 1, 2, preferably m is 0, 1, 2     and n is 1; -   A, B, D, G independently of one another N, C(R42); -   R42 is H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,     (C₃-C₈)-cycloalkyl, (C₀-C₂)-alkylene-aryl, O—(C₀-C₂)-alkylene-aryl,     N(R43)(R44), SO₂—CH₃, COO—(C₁-C₆)-alkyl, CON(R45)(R46),     N(R47)CO(R48), N(R49)SO₂(R50), CO(R51) -   R43, R44, R45, R46, R47, R49     -   independently of one another H, (C₁-C₈)-alkyl; -   R43 and R44, R45 and R46     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur; -   R48, R50, R51     -   independently of one another H, (C₁-C₈)-alkyl, aryl; -   R10 H, (C₁-C₈)-alkyl; -   X N(R52), O, a bond, C═C, C(R53)(R54), C(R55)(R56)O; -   R52, R53, R54, R55, R56     -   independently of one another H, (C₁-C₈)-alkyl -   E 3-8 membered bivalent carbo- or heterocyclic ring structure with     0-4 heteroatoms from the group of N, O and S, which may optionally     have substituents from the group of H, F, Cl, CF₃, NO₂, OH, CN,     O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl,     O—(C₀-C₈)-alkylene-aryl, N(R57)(R58), SO₂—CH₃, COO—(C₁-C₆)-alkyl,     CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64), CO(R65) and may be     mono- or bicyclic, preferably the group E has no substituents from     the group of (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl and     N(R57)(R58), in which R57 and R58 form together with the nitrogen     atom a 5-6 membered ring, in the position ortho to the point of     attachment of X; particularly preferably E is monocyclic; -   R57, R58, R59, R60, R61, R63     -   independently of one another H, (C₁-C₈)-alkyl; -   R57 and R58, R59 and R60     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur, where R59 and R60 are preferably not both H; -   R62, R64, R65     -   independently of one another H, (C₁-C₈)-alkyl, aryl; -   K a bond, O, CH₂O, N(R66), (C(R69)(R70))_(v), C≡C, OCH₂, CON(R68),     preferably a bond, O, CH₂O, ((CR69)(R70))_(v), C≡C, N(R66); -   v 1, 2; -   R66, R68, R69, R70     -   independently of one another H, (C₁-C₈)-alkyl; -   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,     a 3 to 10-membered mono-, bi- or spirocyclic ring which may comprise     0 to 4 heteroatoms selected from the group of oxygen, nitrogen and     sulfur, where the ring system may additionally be substituted by F,     Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,     (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71),     CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77)     or SO₂CH₃, preferably R11 is not COO(R74); -   R71, R72, R73, R74, R75, R76, R77     -   independently of one another H, (C₁-C₈)-alkyl; -   R72 and R73, R76 and R77     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur.

Particularly preferred compounds of the formula I are those in which

-   A, B, D, G are independently of one another N or C(R42), and the     total number of nitrogen atoms in this ring is 0-2, preferably 0 or     1.

Very particularly preferred compounds of the formula I are those in which

-   n is 1 and -   m is 1 or 2.

Especially preferred compounds of the formula I are those in which

-   A, B, D, G are independently of one another N or C(R42) and the     total number of nitrogen atoms in this ring is 0-2, preferably 0 or     1; -   n is 1 and -   m is 1 or 2.

In a further preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are:

-   R1, R2 independently of one another are H, (C₁-C₈)-alkyl,     —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,     CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl,     COCH═CH(R13), COCC(R14), CO(C(R15)(R16))_(q)N(R17)(R18),     CO(C(R19)(R20))_(r)CON(R21 )(R22), CO(C(R23)(R24))_(s)O(R25); or R₁     and R2 form together with the nitrogen atom to which they are bonded     a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from     the nitrogen atom, may comprise 0 to 2 additional heteroatoms     selected from the group of oxygen, nitrogen and sulfur, where the     heterocyclic ring system may additionally be substituted by F, Cl,     CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26),     CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32)     or SO₂CH₃;     -   preferably independently of one another H, (C₁-C₈)-alkyl,         —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, COCH═CH(R13), COCC(R14),         CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R23)(R24))_(s)O(R25);     -   or R₁ and R2 form together with the nitrogen atom to which they         are bonded a 4 to 10-membered mono- or bicyclic ring which,         apart from the nitrogen atom, may comprise 0 to 2 additional         heteroatoms selected from the group of oxygen, nitrogen and         sulfur, where the heterocyclic ring system may additionally be         substituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo,         CO(R26), hydroxy, N(R31)(R32) or SO₂CH₃;     -   particularly preferably independently of one another H,         (C₁-C₈)-alkyl, —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,         CO(C(R15)(R16))_(q)N(R17)(R18), or R1 and R2 form together with         the nitrogen atom to which they are bonded a 4 to 10-membered         mono- or bicyclic ring which, apart from the nitrogen atom, may         comprise 0 to 2 additional heteroatoms selected from the group         of oxygen and nitrogen, where the heterocyclic ring system may         be additionally substituted by F, (C₁-C₆)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, oxo, CO(R26), hydroxy,         N(R31)(R32); -   o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly     preferably 0, 1, 2, 3; -   q, r independently of one another 1, 2, 3; preferably q is 1 or 2; -   s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0,     1, 2; -   R13, R14 independently of one another are a phenyl ring which may     comprise 0-1 nitrogen atoms; -   R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28,     R29, R30, R31, R32     -   independently of one another H, (C₁-C₆)-alkyl; -   R18 H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl, CO(R33); preferably H,     (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl; particularly preferably H,     (C₁-C₆)-alkyl;     or -   R17 and R18, R21 and R22, R27 and R28, R31 and R32     -   independently of one another optionally form together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur; preferably the ring is pyrrolidine, piperidine,         N-methylpiperazine, morpholine; -   R33 a 5-10 membered aromatic ring system which may comprise a     further heteroatom from the group of nitrogen, oxygen and sulfur and     may be substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R12 OH, O—(C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, CN,     S—(C₁-C₆)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi-     or spirocyclic ring which may comprise one or more heteroatoms from     the group of N, O and S, and the 3-12 membered ring may comprise     further substituents such as F, Cl, Br, OH, CF₃, CN, oxo,     O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,     O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),     COCH═CH(R36), (C(R37)(R38))_(t) (R39), CO(C(R37)(R38))_(t) (R39),     CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u) (R41);     -   preferably OH, O—(C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, CN,         3-10 membered mono- or bicyclic ring which may comprise 1-3         heteroatoms from the group of N, O and S, and the 3-10 membered         ring may comprise further substituents such as F, Cl, Br, OH,         CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35),         CO(C₁-C₆)-alkyl;     -   particularly preferably OH, O—(C₁-C₆)-alkyl, 3-10 membered mono-         or bicyclic ring which may comprise 1-2 heteroatoms from the         group of N, O and S, and the 3-10 membered ring may comprise         further substituents such as F, OH, oxo, (C₁-C₆)-alkyl,         CO(C₁-C₆)-alkyl; -   t 0, 1, 2, 3, 4, 5, 6; -   u 0, 1, 2; preferably 0 or 2; particularly preferably 2; -   R34, R35, R37, R38     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R34 and R35     -   optionally together with the nitrogen atom to which they are         bonded a 5-6 membered ring which, apart from the nitrogen atom,         may also comprise 0-1 further heteroatoms from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur and may optionally be         substituted by 1-2 oxo groups; -   R36, R39 independently of one another (C₃-C₈)-cycloalkyl, 5-10     membered aromatic ring system which may comprise 0-2 further     heteroatoms from the group of nitrogen, oxygen and sulfur and may be     substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R40 H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl, (C₀-C₈)-alkylene-aryl; -   R41 (C₁-C₆)-alkyl, 5-10 membered aromatic ring system which may     comprise 0-2 further heteroatoms from the group of nitrogen, oxygen     and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl,     O—(C₁-C₈)-alkyl; -   R78, R79 independently of one another H, (C₁-C₈)-alkyl,     hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; -   R80, R81 independently of one another H, (C₁-C₈)-alkyl; -   R3 H, (C₁-C₆)-alkyl; preferably H; -   R4, R5 independently of one another H, (C₁-C₆)-alkyl, OH,     O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl;     -   preferably independently of one another H, (C₁-C₆)-alkyl, OH,         O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl; particularly preferably         independently of one another H, OH, O—(C₁-C₆)-alkyl; -   R6, R7, R8, R9     -   H;         or -   R6 and R7, R8 and R9     -   independently of one another optionally oxo; -   preferably R6, R7, R8, R9 are H; -   n 1 -   m 1 or 2; preferably 1; -   A, B, D, G independently of one another N, C(R42);     -   or     -   the groups A and B or D and G are each C(R42) and together form         an ortho-phenylene unit to result overall in a 1,4-bisubstituted         naphthalene system;     -   preferably     -   B is N, C(R42); and A, D, G C(R42);     -   particularly preferably     -   A, B, D, G are C(R42); -   R42 H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,     O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,     (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R43)(R44),     SO₂—CH₃, CON(R45)(R46), N(R47)CO(R48), CO(R51),     —(CR84R85)_(x)—O(R86);     -   preferably H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,         (C₁-C₆)-alkyl, SO₂—CH₃, CON(R45)(R46), N(R47)CO(R48), CO(R51),         —(CR84R85)_(x)—O(R86);     -   particularly preferably H, F, Cl, CF₃, CN, (C₁-C₆)-alkyl,         —(CR84R85)_(x)—O(R86); -   R43, R44, R45, R46, R47     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R43 and R44, R45 and R46     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur; -   R48, R50, R51     -   independently of one another H, (C₁-C₈)-alkyl, aryl; preferably         independently of one another H, (C₁-C₈)-alkyl; -   R84, R85 H; -   R86 H, (C₁-C₆)-alkyl; -   x 0, 1, 2; preferably 0, 1; particularly preferably 1; -   R10 H, (C₁-C₈)-alkyl; -   x N(R52), a bond, C═C, C(R53)(R54), C(R55)(R56)O, C≡C, CH₂—CH₂,     YCH₂; preferably N(R52), a bond, C═C, C(R53)(R54), CH₂—CH₂;     particularly preferably a bond, C═C, C(R53)(R54), CH₂—CH_(2;) -   y O, S, N(R89); -   R89 H, (C₁-C₈)-alkyl; -   R52, R53, R54, R55, R56     -   independently of one another H, (C₁-C₈)-alkyl; -   E 3-8 membered bivalent carbo- or heterocyclic ring structure with     0-4 heteroatoms from the group of N, O and S, which may optionally     have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN,     OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,     O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,     (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58),     SO₂—CH₃, N(R61)CO(R62), N(R63)SO₂(R64), CO(R65) and may be mono- or     bicyclic;     -   preferably 5-7 membered bivalent carbo- or heterocyclic ring         structure with 0-3 heteroatoms from the group of N, O and S,         which may optionally have substituents from the group of H, F,         Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,         S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,         O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—CH₃,     -   N(R61)CO(R62), CO(R65) and may be mono- or bicyclic;         particularly preferably 5-7 membered bivalent carbo- or         heterocyclic ring structure with 0-2 heteroatoms from the group         of N, O and S, which may optionally have substituents from the         group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl,         (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65)     -   e.g. E is selected from the group consisting of

which may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65); preferably

which may optionally have the aforementioned substituents;

-   R57, R58, R61, R63     -   independently of one another H, (C₁-C₈)-alkyl; -   R62, R64, R65     -   independently of one another H, (C₁-C₈)-alkyl, aryl; preferably         independently of one another H, (C₁-C₈)-alkyl; -   K a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68),     (C(R69)(R70))_(v), CO, C═C, C≡C, SCH₂, SO₂CH₂; preferably a bond, O,     OCH₂, CH₂O, N(R66), CON(R68), (C(R69)(R70))_(v), CO, C≡C, SCH₂;     particularly preferably a bond, O, OCH₂, CH₂O, CON(R68),     (C(R69)(R70))_(v), CO, C≡C; -   v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2; -   R66, R67, R68, R69, R70     -   independently of one another H, (C₁-C₈)-alkyl; -   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,     (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic     ring, which may comprise 0 to 4 heteroatoms selected from the group     of oxygen, nitrogen and sulfur, where the ring system may     additionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,     O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl hydroxy-(C₁-C₄)-alkyl,     (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy,     COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃;     -   preferably (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to         10-membered mono-, bi-, tri- or spirocyclic ring which may         comprise 0 to 3 heteroatoms selected from the group of oxygen,         nitrogen and sulfur, where the ring system may additionally be         substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,         O—(C₁-C₈)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R71),         CON(R72)(R73), hydroxy, N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or         SO₂CH₃;     -   particularly preferably (C₁-C₈)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or         bicyclic ring which may comprise 0 to 2 heteroatoms selected         from the group of oxygen, nitrogen and sulfur, where the ring         system may additionally be substituted by F, Cl, Br, CF₃, CN,         (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R71), CON(R72)(R73),         N(R75)CO(C₁-C₆)-alkyl, or SO₂CH₃; -   R71, R72, R73, R74, R75, R76, R77     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R72 and R73, R76 and R77     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur; or         the N-oxides and the physiologically tolerated salts thereof.

In a further preferred embodiment, A, B, G and D in formula I are CH or:

If E is 1,4-phenylene, the preferred meanings for A, B, G and D are furthermore those listed in table I below:

TABLE I A B G D N CH CH CH CH N CH CH C—Cl N CH CH C—F CH C—F CH CH CH C—F CH CH C—F CH CH CH CH CH CF CH C—Br CH CH CH CH C—Br CH CH C—Cl CH CH CH CH C—Cl CH CH CH C—CN CH CH CH CH C—CN CH CH C—CH₃ CH CH CH CH C—CH₃ CH CH C—CF₃ CH CH CH CH C—CF₃ CH CH CH CH₂OH CH C—F CH C—F CH C—F C—F CH CH CH C—F C—F CH CH C—F C—Cl CH CH C—Cl C—CN CH C—CH₃ C—Cl CH CH N CH C—CH₃ CH C—CH₃ CH N CH N C—CH₃ CH CH CH

If E is

the preferred meanings for A, B, G and D are furthermore those listed in table 11 below:

TABLE II A B G D CH C—CH₃ CH CH CH C—F CH CH CH CH C—CH₃ CH CH CH C—F CH CH N CH CH CH CH CH N C—F CH C—F CH

If E is

the preferred meanings for A, B, G and D are furthermore those listed in table III below:

TABLE III A B G D CH CH C—F CH CH N CH CH CH CH CH N

Further preferred combinations for E and A, B, G and D are listed in table IV.

TABLE IV E A B G D

CH C—F CH CH

CH CH C—F CH

CH C—F CH CH

CH C—F CH CH

CH CF CH CH

CH CF CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

CH C—F CH CH

The radicals R11, K, X and E in formula I have in a particularly preferred embodiment one of the following meanings:

R11is preferably selected from the group consisting of:

-   n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluorophenyl,     p-chlorophenyl, p-bromophenyl, p-tolyl, p-methoxyphenyl,     p-trifluoromethylphenyl, p-methylthiophenyl, o-fluorophenyl,     o-chlorophenyl, o-cyanophenyl, m-fluorophenyl, 2,4-difluorophenyl,     3-fluoro-4-methylphenyl, 2-nitro-4-methylphenyl,     2-amino-4-methylphenyl,

K is preferably selected from the group consisting of:

-   —O—, bond, C≡C, CH₂, CH₂O, CONH, OCH₂, CO, SCH₂ and (CH₂)₂O.

X is preferably selected from the group consisting of bond, NH and CH₂.

E is preferably selected from the group consisting of:

Preferred combinations of R11, K, X and E are listed below:

If K and X are each a bond, the particularly preferred meanings for E and R11 areas follows:

-   -   If E is 1,4-phenylene, R11 is selected from the group consisting         of:         -   cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl,             p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl,             2,4-difluorophenyl, 3-fluoro-4-methylphenyl, o-cyanophenyl,

-   -   If E is

R 11 selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl, o-fluorophenyl, phenyl and

Further combinations of E and R11 or the case where K and X are each a bond are listed in table V:

TABLE V R11 E p-Chlorophenyl 1,4-Cyclohexylene 2-Nitro-4-methylphenyl

p-Chlorophenyl

p-Bromophenyl

p-Fluorophenyl

p-Chlorophenyl

p-Tolyl

n-Butyl

p-Chlorophenyl

p-Methylthiophenyl

2-Amino-4-methylphenyl

If K is —O— and X is a bond, NH or CH₂, the particularly preferred meanings for E and R11 are as follows:

-   -   If E is 1,4-phenylene, R11 is selected from the group consisting         of:     -   phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl,         2,4-difluorophenyl and p-fluorophenyl.

Further combinations of E and R11 for the case where K is —O— and X is a bond, NH or CH₂ are listed in table VI:

TABLE VI R11 E Phenyl

Cyclopentyl

Phenyl

n-Butyl

n-Butyl

If K is C≡C and X is a bond, the particularly preferred meanings of E and R11 are as follows:

-   -   If E is

R11 is selected from the group consisting of:

-   -   phenyl, p-fluorophenyl and p-chlorophenyl.

If K is CH₂ and X is a bond, the particularly preferred meanings of E and R11 are indicated in table VII below:

TABLE VII R11 E Phenyl 1,4-Phenylene

1,4-Phenylene p-Chlorophenyl

If K is CH₂O and X is a bond, the particularly preferred meanings of E and R11 areas follows:

-   -   If E is 1,4-phenylene, R11 is selected from the group consisting         of:         -   phenyl, cyclopropyl and cyclohexyl.

If K is CONH and X is a bond, the particularly preferred meanings of E and R11 are indicated in table VIII below:

TABLE VIII R11 E Cyclopentyl 1,4-Phenylene Cyclohex-(1)-enyl 1,4-Phenylene Cyclopentyl

If K is OCH₂ and X is a bond, the particularly preferred meanings of E and R11 are indicated in table IX below:

TABLE IX R11 E o-Chlorophenyl

p-Tolyl 1,4-Phenylene n-Propyl 1,4-Phenylene Cyclobutyl 1,4-Phenylene

The combinations of R11, K and E listed in table X below are furthermore particularly preferred in addition to the aforementioned combinations, with X very particularly preferably being a bond:

TABLE X R11 K E o-Fluorophenyl CO

Phenyl SCH₂ 1,4-Phenylene Cyclopropyl (CH₂)₂O

The compounds of the formula I are in a very particularly preferred embodiment compounds of the formula Ia

in which the radicals R1, R2, R10, R11, R42, and groups X, E, K have the aforementioned meanings, and R42′ is defined as R42, where R42 and R42′ in the compounds of the formula Ia may be identical or different, or the N-oxides and the physiologically tolerated salts thereof.

In a preferred embodiment of the invention, the radicals R1, R2, R10, R11, R42, R42′ and groups X, E, K have the following meanings:

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,     —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2 form     together with the nitrogen atom to which they are bonded a 4 to     10-membered mono-, bi- or spirocyclic ring which, apart from the     nitrogen atom, may comprise 0 to 2 additional heteroatoms selected     from the group of oxygen, nitrogen and sulfur, where the     heterocyclic ring system may additionally be substituted by F,     (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26),     CON(R27)(R28), hydroxy, N(R31)(R32) or SO₂CH₃; where R¹ and R² are     not both CO(R26),     -   preferably H, (C₁-C₈)-alkyl, —(CR78R79)_(o)—R12,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2 form together with         the nitrogen atom to which they are bonded a 4 to 10-membered         mono- or bicyclic ring which, apart from the nitrogen atom, may         comprise 0 to 2 additional heteroatoms selected from the group         of oxygen and nitrogen, where the heterocyclic ring system may         additionally be substituted by F, (C₁-C₆)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, oxo, CO(R26), hydroxy,         N(R31)(R32); -   o 0, 1, 2, 3, 4, preferably     -   0, 1, 2, 3; -   q 1, 2, 3, preferably     -   1 or 2; -   s 0, 1, 2; -   R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32     -   independently of one another H, (C₁-C₆)-alkyl;         or -   R17 and R18, R27 and R28, R31 and R32     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur, preferably the ring is a pyrrolidine, piperidine,         N-methylpiperazine, morpholine ring; -   R12 OH, O—(C₁-C₆)-alkyl, O—(C₀-C₂)-alkylene-aryl, CN,     S—(C₁-C₆)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which     may comprise 1 to 3 heteroatoms from the group of N, O and S, and     the 3-12 membered ring may comprise further substituents such as F,     OH, CF₃, CN, oxo, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35),     COO(R40), CO(C₁-C₆)-alkyl, preferably OH, O—(C₁-C₆)-alkyl, 3-10     membered mono- or bicyclic ring which may comprise 1-2 heteroatoms     from the group of N, O and S, and the 3-10 membered ring may     comprise further substituents such as F, OH, oxo, (C₁-C₆)-alkyl,     CO(C₁-C₆)-alkyl; -   R34, R35     -   independently of one another H, (C₁-C₄)-alkyl; -   R40 H, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl; -   R78, R79 independently of one another H, (C₁-C₈)-alkyl,     hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; -   R42, R42′ independently of one another H, F, Cl, Br, CF₃, CN,     (C₁-C₆)-alkyl; -   R10 H, (C₁-C₈)-alkyl; -   X N(R52), a bond, C═C, C(R53)(R54), CH₂CH₂; -   R52, R53, R54     -   

independently of one another H, (C₁-C₈)-alkyl;

-   E 5-7 membered bivalent carbo- or heterocyclic ring structure with     0-3 heteroatoms from the group of N, O and S, which may optionally     have substituents from the group of H, F, Cl, Br, CF₃, OH, CN, OCF₃,     NO₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃, CO(R65);     -   preferably 5-7 membered bivalent carbo- or heterocyclic ring         structure with 0-2 heteroatoms from the group of N, O and S,         which may optionally have substituents from the group of H, F,         Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,         (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65) e.g. E is         selected from the group consisting of

which may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65); preferably

which may optionally have the aforementioned substituents;

-   R65 H, (C₁-C₈)-alkyl; -   K a bond, O, OCH₂, CH₂O, S, SO₂, N(R66), N(R67)CO, CON(R68),     (C(R69)(R70))_(v), CO, C≡C, SCH₂, SO₂CH₂;     -   preferably a bond, O, OCH₂, CH₂O, CON(R68), (C(R69)(R70))_(v),         particularly preferably CH₂, CO, C≡C; -   v 1, 2, 3, preferably     -   1, 2; -   R66, R67, R68, R69, R70     -   independently of one another H, (C₁-C₈)-alkyl; -   R11 (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered     mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4     heteroatoms selected from the group of oxygen, nitrogen and sulfur,     where the ring system may additionally be substituted by F, Cl, Br,     CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R71), hydroxy,     N(R75)CO(C₁-C₆)-alkyl, or SO₂CH₃;     -   preferably (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to         10-membered mono- or bicyclic ring which may comprise 0 to 2         heteroatoms selected from the group of oxygen, nitrogen and         sulfur, where the ring system may additionally be substituted by         F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo,         CO(R71), CON(R72)(R73), N(R75)CO(C₁-C₆)-alkyl, or SO₂CH₃; -   R71, R72, R73, R74, R75, R76, R77     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R72 and R73, R76 and R77     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur.

In a preferred embodiment, the present invention relates to compounds of the formula Ia,

in which

-   X is CH₂CH₂, N(R52), CH₂, OCH₂, SCH₂, CH═CH, preferably CH₂CH₂,     CH═CH; -   E is

-   K is a bond, O or C(R69)(R70);     and the other symbols R1, R2, R10, R11, R42, R42′, R52, R69 and R70     have the meanings indicated above in relation to a definition of the     radicals of the compound of the formula Ia.

In a further preferred embodiment, the present invention relates to compounds of the formula Ia,

in which

-   X is N(R52), preferably NH, or C(R53)(R54); -   E is

-   K is a bond, O or C(R69)(R70), preferably 0;     -   preferably O         and the other symbols R1, R2, R10, R11, R42, R42′, R52, R53,         R54, R69 and R70 have the meanings indicated above in relation         to a definition of the radicals of the compound of the formula         Ia.

In a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula Ib

in which the radicals R1, R2, R10 and R11 and the groups E and D have the aforementioned meanings, or the N-oxides and the physiologically tolerated salts thereof.

In a preferred embodiment, the radicals R1, R2, R10 and R11 the groups E and D have the following meanings:

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,     —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,     CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl,     COCH═CH(R13), COCC(R14), CO(C(R15)(R16))_(q)N(R17)(R18),     CO(C(R19)(R20))_(r)CON(R21)(R22), CO(C(R23)(R24))_(s)O(R25); or R1     and R2 form together with the nitrogen atom to which they are bonded     a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from     the nitrogen atom, may comprise 0 to 2 additional heteroatoms     selected from the group of oxygen, nitrogen and sulfur, where the     heterocyclic ring system may additionally be substituted by F, Cl,     CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26),     CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32)     or SO₂CH₃, where R1 and R2 are not both CO(R26);     -   preferably independently of one another H, (C₁-C₈)-alkyl,         —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, COCH═CH(R13), COCC(R14),         CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R23)(R24))_(s)O(R25);     -   or R1 and R2 form together with the nitrogen atom to which they         are bonded a 4 to 10-membered mono- or bicyclic ring which,         apart from the nitrogen atom, may comprise 0 to 2 additional         heteroatoms selected from the group of oxygen, nitrogen and         sulfur, where the heterocyclic ring system may additionally be         substituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo,         hydroxy, N(R31)(R32) or SO₂CH₃, where R1 and R2 are not both         CO—(C₁-C₈)-alkyl;     -   particularly preferably independently of one another H,         (C₁-C₈)-alkyl, —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,         CO(C(R15)(R16))_(q)N(R17)(R18), or R1 and R2 form together with         the nitrogen atom to which they are bonded a 4 to 10-membered         mono- or bicyclic ring which, apart from the nitrogen atom, may         comprise 0 to 2 additional heteroatoms selected from the group         of oxygen and nitrogen, where the heterocyclic ring system may         additionally be substituted by F, (C₁-C₆)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, oxo, CO(C₁-C₈)-alkyl, hydroxy,         N(R31)(R32), where R1 and R2 are not both CO(C₁-C₈)-alkyl; -   o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly     preferably 0, 1, 2, 3; -   q, r independently of one another 1, 2, 3; preferably q is 1 or 2; -   s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0,     1, 2; -   R13, R14 independently of one another a phenyl ring which may     comprise 0-1 nitrogen atoms; -   R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28,     R29, R30, R31, R32     -   independently of one another H, (C₁-C₆)-alkyl; -   R18 H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl, CO(R33); preferably H,     (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl; particularly preferably H,     (C₁-C₆)-alkyl;     or -   R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of     one another optionally together with the nitrogen atom to which they     are bonded a 5-6 membered ring which, apart from the nitrogen atom,     may also comprise 0-1 further heteroatoms from the group of     N—(C₁-C₆)-alkyl, oxygen and sulfur; preferably the ring is     pyrrolidine, piperidine, N-methylpiperazine, morpholine; -   R33 a 5-10 membered aromatic ring system which may comprise a     further heteroatom from the group of nitrogen, oxygen and sulfur and     may be substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R12 is OH, O—(C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, CN,     S—(C₁-C₆)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi-     or spirocyclic ring which may comprise one or more heteroatoms from     the group of N, O and S and the 3-12 membered ring may comprise     further substituents such as F, Cl, Br, OH, CF₃, CN, oxo,     O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,     O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),     COCH═CH(R36), (C(R37)(R38))_(t) (R39), CO(C(R37)(R38)) (R39),     CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u) (R41);     -   preferably OH, O—(C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, CN,         3-10 membered mono- or bicyclic ring which may comprise 1-3         heteroatoms from the group of N, O and S, and the 3-10 membered         ring may comprise further substituents such as F, Cl, Br, OH,         CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,         (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35),         CO(C₁-C₆)-alkyl;     -   particularly preferably OH, O—(C₁-C₆)-alkyl, 3-10 membered mono-         or bicyclic ring which may comprise 1-2 heteroatoms from the         group of N, O and S and the 3-10 membered ring may comprise         further substituents such as F, OH, oxo, (C₁-C₆)-alkyl,         CO(C₁-C₆)-alkyl; -   t 0, 1, 2, 3, 4, 5, 6; -   u 0, 1, 2; preferably 0 or 2; particularly preferably 2; -   R34, R35, R37, R38     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R34 and R35     -   optionally together with the nitrogen atom to which they are         bonded a 5-6 membered ring which, apart from the nitrogen atom,         may also comprise 0-1 further heteroatoms from the group of         N—(C₁-C₆)-alkyl, oxygen and sulfur and may optionally be         substituted by 1-2 oxo groups; -   R36, R39 independently of one another (C₃-C₈)-cycloalkyl, 5-10     membered aromatic ring system which may comprise 0-2 further     heteroatoms from the group of nitrogen, oxygen and sulfur and may be     substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; -   R40 H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl, (C₀-C₈)-alkylene-aryl; -   R41 (C₁-C₆)-alkyl, 5-10 membered aromatic ring system which may     comprise 0-2 further heteroatoms from the group of nitrogen, oxygen     and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl,     O—(C₁-C₈)-alkyl; -   R78, R79 independently of one another H, (C₁-C₈)-alkyl,     hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; -   R80, R81 independently of one another H, (C₁-C₈)-alkyl; -   R10 H, (C₁-C₈)-alkyl; -   E 3-8 membered bivalent carbo- or heterocyclic ring structure with     0-4 heteroatoms from the group of N, O and S, which may optionally     have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN,     OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alky     S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,     O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,     (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58),     SO₂—CH₃, N(R61 )CO(R62), N(R63)SO₂(R64), CO(R65) and may be mono- or     bicyclic;     -   preferably 5-7 membered bivalent carbo- or heterocyclic ring         structure with 0-3 heteroatoms from the group of N, O and S,         which may optionally have substituents from the group of H, F,         Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,         S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,         O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—CH₃, N(R61         )CO(R62), CO(R65) and may be mono- or bicyclic;     -   particularly preferably 5-7 membered bivalent carbo- or         heterocyclic ring structure with 0-2 heteroatoms from the group         of N, O and S, which may optionally have substituents from the         group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl,         (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65)     -   e.g. E is selected from the group consisting of

which may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65); preferably

which may optionally have the aforementioned substituents;

-   R57, R58, R61, R63     -   independently of one another H, (C₁-C₈)-alkyl; -   R62, R64, R65     -   independently of one another H, (C₁-C₈)-alkyl, aryl; preferably         independently of one another H, (C₁-C₈)-alkyl; -   K a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68),     (C(R69)(R70))_(v), CO, C═C, C≡C, SCH₂, SO₂CH₂;     -   preferably a bond, O, OCH₂, CH₂O, N(R66), CON(R68),         (C(R69)(R70))_(v), CO, C≡C, SCH₂; particularly preferably a         bond, O, OCH₂, CH₂O, CON(R68), (C(R69)(R70))_(v), CO, C≡C; -   v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2; -   R66, R67, R68, R69, R70     -   independently of one another H, (C₁-C₈)-alkyl; -   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,     (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic     ring which may comprise 0 to 4 heteroatoms selected from the group     of oxygen, nitrogen and sulfur, where the ring system may     additionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,     O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,     hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71),     CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77)     or SO₂CH₃SCF₃;     -   preferably (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to         10-membered mono-, bi-, tri- or spirocyclic ring which may         comprise 0 to 3 heteroatoms selected from the group of oxygen,         nitrogen and sulfur, where the ring system may additionally be         substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,         O—(C₁-C₈)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R71),         CON(R72)(R73), hydroxy, N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or         SO₂CH₃;     -   particularly preferably (C₁-C₈)-alkyl,         (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or         bicyclic ring which may comprise 0 to 2 heteroatoms selected         from the group of oxygen, nitrogen and sulfur, where the ring         system may additionally be substituted by F, Cl, Br, CF₃, CN,         (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R71), CON(R72)(R73),         N(R75)CO(C₁-C₆)-alkyl, or SO₂CH₃; -   R71, R72, R73, R74, R75, R76, R77     -   independently of one another H, (C₁-C₈)-alkyl;         or -   R72 and R73, R76 and R77     -   independently of one another optionally together with the         nitrogen atom to which they are bonded a 5-6 membered ring         which, apart from the nitrogen atom, may also comprise 0-1         further heteroatoms from the group of N—(C₁-C₆)-alkyl, oxygen         and sulfur.

In a preferred embodiment, the present invention relates to compounds of the formula Ib

in which

-   X is a bond, -   E is

where the aforementioned groups may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂—CH₃, CO(R65); preferably E is

in which the groups may have the aforementioned substituents;

-   K is a bond; and     the other radicals R1, R2, R10 and R11 and the group D have the     meanings indicated above in relation to the definition of the     radicals of the compound of the formula Ib.

R11 in the aforementioned compounds of the formula Ib is particularly preferably a substituted mono- or bicyclic ring system with 5-10 members, which may have 0-3 heteroatoms, in particular N, O and/or S, particularly preferably phenyl with 0-1 N atom, cyclohexyl or a bicyclic system with 8-10 members and 1-2 heteroatoms, in particular N, O and/or S.

In a further preferred embodiment, the present invention relates to compounds of the formula Ib

in which

-   X is a bond; -   E is

where the aforementioned groups may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R57)(R58), SO₂CH₃ and CO(R65); preferably

in which the groups may have the aforementioned substituents;

-   K is CH₂, CH₂CH₂, O, CH₂O, OCH₂, CON(R68), N(R67)CO, S, SO₂, SCH₂,     SO₂, SO₂CH₂, CO or a triple bond;     -   preferably CH₂, O, CH₂O, OCH₂, CON(R68), SCH₂, CO or a triple         bond; and         the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11,         R67 and R68 and the group D have the meanings indicated above in         relation to the definition of the radicals of the compound of         the formula Ib.

The amount of a compound of formula (I) necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the free compound from which the salt is derived. For the prophylaxis and therapy of the abovementioned conditions, the compounds of formula (I) may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula (I). The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula (I) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

As used herein, the following definitions apply:

“Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

“Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

The compounds of the formula I are distinguished by beneficial effects on lipid metabolism, and they are particularly suitable for weight reduction and for maintaining a reduced weight after weight reduction has taken place in mammals and as anorectic agents. The compounds are distinguished by their low toxicity and their few side effects. The compounds can be employed alone or in combination with other weight-reducing or anorectic active ingredients. Further anorectic active ingredients of this type are mentioned, for example, in the Rote Liste, chapter 01 under weight-reducing agents/appetite suppressants, and they also include active ingredients which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of the organism in such a way that an increased calorie intake does not lead to an enlargement of the fat depots and a normal calorie intake leads to a reduction of the fat depots of the organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of excessive weight or obesity. The compounds are further suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of arteriosclerosis and for normalizing lipid metabolism and for the treatment of high blood pressure. The compounds act as MCH antagonists and are also suitable for the treatment of disturbances of wellbeing and of psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.

In a further aspect of the invention, the compounds of the formula I can be administered in combination with one or more other pharmacologically active substances which are selected, for example, from antidiabetics, antiobesity agents, active ingredients which lower blood pressure, lipid-lowering agents and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

Further pharmacologically active substances suitable in particular are:

-   all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They     may be combined with the compounds of the formula I of the invention     in particular for a synergistic improvement of the effect.     Administration of the active ingredient combination may take place     either by separate administration of the active ingredients to the     patient or in the form of combination products in which a plurality     of active ingredients are present in one pharmaceutical preparation.     Most of the active ingredients listed below are disclosed in the USP     Dictionary of USAN and International Drug Names, US Pharmacopeia,     Rockville 2001.

Suitable antidiabetics include insulin and insulin derivatives such as, for example, Lantus® or HMR 1964, fast-acting insulins (see U.S. Pat. No. 6,221,633), amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally effective hypoglycemic active ingredients.

The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, e.g. HMGCoA reductase inhibitors, inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the present compounds are administered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490, DE10142734.4.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757.

In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No. 6,221,897), such as, for example, HMR 1741.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), such as, for example, HMR1171, HMR1586.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyse inhibitor, such as, for example, SB-204990.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat.

In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.

In one further embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidined

In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor, such as, for example, miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. The compounds of the invention may moreover be administered in combination with one or more antiobesity agents or appetite-controlling active ingredients.

In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexyl-methyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethy]-amide; (WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, β3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the other active ingredient is leptin; see, for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the other active ingredient is dexamphatamine or amphetamine.

In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the other active ingredient is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine.

In one embodiment, the other active ingredient is orlistat.

In one embodiment, the other active ingredient is mazindol or phentermine.

In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October), 18(5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.

The present compounds may additionally be administered in combination with one or more antihypertensive active ingredients. Examples of antihypertensive active ingredients are beta blockers such as alprenolol,atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil, prazosin and terazosin. Reference may furthermore be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, Pa., 1995.

It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention.

The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.

The present invention is not to be limited in scope by the specific embodiments describe herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

EXAMPLES

The efficacy of the compounds was tested as follows:

Biological Test Model:

The anorectic effect was tested on female NMRI mice. After withdrawal of food for 17 hours, the test product was administered by gavage. The animals were housed singly with free access to drinking water and were offered condensed milk 30 minutes after administration of the product. The condensed milk consumption was determined every half hour for 7 hours, and the general wellbeing of the animals was observed. The measured milk consumption was compared with the vehicle-treated control animals.

TABLE 1 Anorectic effect measured as the reduction in the cumulative milk consumption of treated compared with control animals Number of Number of Reduction in animals/- animals/- the cumulative milk cumulative milk cumulative consumption of consumption of milk Oral the treated the control consumption dose animals animals as % of the Example [mg/kg] N/[ml] N/[ml] control Example 4 30 5/3.55 5/1.76 50 Example 30 5/3.70 5/1.34 64 13

DESCRIPTION OF EXPERIMENTS

Functional Measurements to Find IC50 Values

The cloning of the cDNA for the human MCH receptor, preparation of a recombinant HEK293 cell line which expresses the human MCH receptor, and functional measurements with the recombinant cell line took place in analogy to the description by Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). A difference from the reference was, however, the use of the plasmid pEAK8 from EDGE Biosystems (USA) to construct the expression vector. The host used for the transfection was a transformed HEK cell line named “PEAK Stable Cells” (likewise from EDGE Biosystems). The functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligand of the invention took place with the aid of the FLIPR apparatus from Molecular Devices (USA) using the protocols of the apparatus manufacturer.

The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it.

The compounds of the formula I of the invention can be prepared with the aid of reactions which are known in principle. For example, the compounds were obtained in accordance with the following general reaction schemes.

Other compounds of the invention can be obtained by further routes which are outlined by way of example in the following scheme.

Yet other examples were obtained as indicated in the following scheme.

Descriptions of the general methods used are to be found by way of example described at the following places:

-   Methods A, B and C in example 1; -   Method D in example 2; -   Method E in example 3; -   Method E-a in example 275; -   Method E-b in example 286; -   Method F in example 4; -   Method F-a in example 264; -   Method G in example 15; -   Method H in example 237; -   Method H-a in example 298; -   Method I in example 238; -   Method J in example 245; -   Method J-a in example 297; -   Method K in example 250; -   Method L in example 254; -   Method M in example 274; -   Method N in example 277; -   Method O in example 279; -   Method O-a in example 292; -   Method O-b in example 280; -   Method P in example 285; -   Method Q in example 290; -   Method R in example 309.     General Explanations     a) Mode of Drawing the Structural Formulae

Only non-hydrogen atoms are depicted for clarity in the structural formulae of the given examples.

In tables 6-13, enantiomer-enriched compounds are identified by a marked hydrogen atom on the stereogenic center. Unless expressly noted otherwise, the enantiomer-enriched examples shown have the (R) configuration on the 3-aminopyrrolidine stereocenter.

b) Salt Forms

Many of the compounds of the invention are bases and can form salts with appropriately strong acids. In particular, after purification of the compounds by HPLC chromatography using a trifluoroacetic acid-containing mobile phase they may be in the form of hydrotrifluoroacetates. These can be converted into the free bases shown by simple treatment of a solution of the salts for example with sodium carbonate solution.

c) Units of the Characterizing Data

The unit of the stated molecular weight is “g/mol”. Peaks observed in the mass spectrum are indicated as the integral quotient of the molar molecular ion mass and the charge of the molecular ion (m/z).

Example 1 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

Method A

A solution of 4-phenoxyaniline (3.33 g) in DMF (10 ml) was added dropwise to a solution of carbonyldiimidazole (2.92 g) in DMF (12 ml) cooled to 0° C. After 30 minutes, N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (3.80 g) in DMF (10 ml) was added dropwise. The reaction solution was kept initially at room temperature for 2 hours and then at 80° C. for 30 minutes. The mixture was added dropwise to water (600 ml) and the resulting precipitate was filtered off with suction and washed with water. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide

Method B

A suspension of N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (3.5 g) and palladium(II) hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was vigorously stirred under a hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).

N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

Method C

4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).

Example 2 1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

Method D

A mixture of N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrroldin-3-yl)acetamide (6.0 g), ethanol (250 ml), water (60 ml) and sodium hydroxide solution (10 M; 80 ml) was heated under reflux for 12 hours. The alcohol was distilled out and the resulting precipitate was filtered off with suction and washed with dichloromethane. Additional product was obtained by concentration of the organic phase and chromatography (silica gel, dichloromethane/methanol 9:1 with 1% triethylamine). This resulted in the product with the molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).

Example 3 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-2-phenylacetamide

Method E

TOTU (327 mg) was added to a solution of 1-[4-(3-methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea (402 mg) in DMF (3 ml) at 0° C. After 10 minutes, Hünig's base (130 mg) and then a solution of phenylacetic acid (136 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 520.64 (C32H32N4O3); MS (ESI): 521 (M+H+) as hydrotrifluoroacetate.

Example 4 (R)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxyaniline by method A. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide

(R)-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).

(R)-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

Method F

(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).

(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide

(R)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).

Example 5 (S)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

The sequence described in example 4 was applied to (S)-N-pyrrolidin-3-ylacetamide. This resulted in the product with the molecular weight of 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).

Example 6 (R)-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

(R)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide was reacted by method D. This resulted in the product with the molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).

Example 7 (S)-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

(S)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide was reacted by method D. This resulted in the product with the molecular weight of 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).

Example 8 (R)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl)-N-methylacetamide was reacted with 4-cyclopentyloxyaniline by method A. This resulted in the product with the molecular weight of 436.56 (C25H32N4O3); MS (ESI): 437 (M+H+).

(S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide was obtained analogously from (S)-N-[1-(4-amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide.

4-Cyclopentyloxyaniline

A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 ml) was heated at 80° C. for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 (M+H+).

Example 9 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea

N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was reacted by method D. This resulted in the product with the molecular weight of 394.52 (C23H30N4O2); MS (ESI): 395 (M+H+).

(R)- and (S)-1-(4-cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1-yl)-phenyl]-urea was obtained analogously from (R)- and (S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide.

Example 10 Ethyl (1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-carbamate

Ethyl chloroformate (8 μl) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 466.59 (C26H34N4O4); MS (ESI): 467 (M+H+) as hydrotrifluoroacetate.

Example 11 1-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1-methylurea

Ethyl isocyanate (7 μl) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 465.60 (C26H35N5O3); MS (ESI): 466 (M+H+) as hydrotrifluoroacetate.

Example 12 1-(4-Cyclopentyloxyphenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2-ylmethyl)amino]pyrrolidin-1-yl}phenyl)urea

(R)-5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1-yl)phenyl]urea (30 mg) and potassium carbonate (20 mg) in DMF (3 ml). After 2 hours, the reaction mixture was filtered and concentrated, and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.64 (C28H37N5O3); MS (ESI): 492 (M+H+) as hydrotrifluoroacetate.

Example 13 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 455.00 (C25H31ClN4O2); MS (ESI): 455 (M+H+).

(R)- and (S)-4-(4-chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide were obtained analogously from (R)- and (S)-N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide.

Example 14 tert-Butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}-phenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 513.09 (C28H37ClN4O3); MS (ESI): 513 (M+H+).

tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was hydrogenated by method B. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+).

tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

tert-Butyl (R)-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).

Example 15 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide

Method G

Trifluoroacetic acid (6.67 g) was added to a solution of tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate (1.5 g) in dichloromethane (50 ml). After 3 hours, volatile fractions were removed and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 412.97 (C23H29ClN4O); MS (ESI): 413 (M+H+).

Example 16 4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-{(R)-3-[methyl-(1-methyl-piperidin-3-ylcarbonyl)amino]pyrrolidin-1-yl}phenyl)amide

(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).

Example 17 4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-(R)-{3-[methyl-(2-piperidin-1-ylacetyl)amino]pyrrolidin-1-yl}phenyl)amide

(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).

Example 18 4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-(R)-{3-[methyl-(2-oxo-thiazolidine-4-carbonyl)amino]pyrrolidin-1-yl}phenyl)amide

(R)-4-(4-Chlorophenyl)piperidin-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 542.10 (C27H32ClN5O3S); MS (ESI): 542 (M+H+).

Example 19 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-{3-[methyl-(2,2,2-trifluoroacetyl)amino]pyrrolidin-1-yl}phenyl)amide

(R)-[N-[1-(4-aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)-piperidine by method A. This resulted in the product with the molecular weight of 508.98 (C25H28ClF3N4O2); MS (ESI): 509 (M+H+).

(R)-[N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide

(R)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 287.29 (C13H16F3N3O); MS (ESI): 288 (M+H+).

(R)-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution of (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine (0.48 g) in pyridine (2 ml). After 3 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with citric acid solution, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 317.27 (C13H14F3N3O3); MS (ESI): 318 (M+H+).

(R)-Methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]amine

A solution of tert-butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]-carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction solution was concentrated and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 221.26 (C11H15N3O2); MS (ESI): 222 (M+H+).

Example 20 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}methylamide

4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide was reacted with iodomethane by method F. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).

Example 21 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-{3-[acetyl-(2-diethylaminoethyl)amino]pyrrolidin-1-yl}phenyl)amide

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide was reacted with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 540.15 (C30H42ClN5O2); MS (ESI): 540 (M+H+).

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide (R)-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).

(R)-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

(R)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).

Example 22 1-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-phenoxyaniline by method A, B and C. This resulted in the product with the molecular weight of 416.53 (C25H28N4O2); MS (ESI): 417 (M+H+).

Example 23 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-isobutoxyphenyl)propionamide

N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 2-(4-isobutoxyphenyl)propionic acid by method E. This resulted in the product with the molecular weight of 437.59 (C26H35N3O3); MS (ESI): 438 (M+H+).

Example 24 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

N-Pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 422.53 (C24H30N4O3); MS (ESI): 423 (M+H+).

(R)- and (S)-N-(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide were obtained in an analogous manner starting from (R)- and (S)-N-pyrrolidin-3-ylacetamide.

Example 25 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-ethylacetamide

N-Ethyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 450.59 (C26H34N4O3); MS (ESI): 451 (M+H+).

Example 26 4-(4-Chlorophenyl)piperidin-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]-3-methylphenyl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1-fluoro-2-methyl-4-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).

Example 27 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl)-3-fluorophenyl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,2-difluoro-4-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).

Example 28 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2,6-difluorophenyl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,3,5-trifluoro-2-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).

Example 29 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-methylphenyl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoro-2-methyl-1-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).

Example 30 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-fluorophenyl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2,4-difluoro-1-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).

Example 31 tert-Butyl (R)-[1-(5-{[4-(4-Chlorophenyl)piperidin-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3yl]methylcarbamate

The synthetic sequence for preparing tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate was carried out starting from 2-chloro-5-nitropyridine instead of 4-fluoronitrobenzene. This resulted in the product with the molecular weight of 514.07 (C27H36ClN5O3); MS (ESI): 514 (M+H+).

Example 32 (R)-[4-(4-Chlorophenyl)piperidine-1-carboxylic acid [6-(3-methylamino-pyrrolidin-1-yl)pyridin-3-yl]amide

tert-Butyl (R)-[1-(5-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3yl]methylcarbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 413.95 (C22H28ClN5O); MS (ESI): 414 (M+H+).

It was possible to obtain racemic [4-(4-chlorophenyl)piperidine-1-carboxylic acid [6-(3-methylaminopyrrolidin-yl)pyridin-3-yl]amide in a similar manner.

Example 33 4-(4-Chlorophenyl)piperidine-1-carboxylic acid {6-[3-(acetylmethylamino)-pyrrolidin-1-yl]pyridin-3-yl}amide

N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2-chloro-5-nitro-pyridine, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).

Example 34 1-[4-(4-Dimethylaminopiperidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea

Dimethylpiperidin-4-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline ([1-(4-aminophenyl)piperidin-4-yl]dimethylamine) was reacted with CDI and 4-phenoxyaniline by method A, B and C. This resulted in the product with the molecular weight of 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+).

Example 35 1-(4-Cyclopentyloxyphenyl)-3-[4-(4-morpholin-4-ylpiperidin-1-yl)phenyl]urea

4-Piperidin-4-ylmorpholine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 464.61 (C27H36N4O3); MS (ESI): 465 (M+H+).

Example 36 4-Butoxy-N-[4-(4-dimethylaminopiperidin-1-yl)phenyl]benzamide

([1-(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4-4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 395.55 (C24H33N3O2); MS (ESI): 396 (M+H+).

Example 37 4-(4-Chlorophenyl)piperidin-1-carboxylic acid {4-[3-(acetylmethylamino)-azetidin-1-yl]phenyl}amide

N-[1-(4-aminophenyl)azetidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 440.98 (C24H29ClN4O2); MS (ESI): 441 (M+H+).

N-[1-(4-Aminophenyl)azetidin-3-yl]-N-methylacetamide

N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).

N-Methyl-N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide

N-[1-(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).

N-[1-(4-Nitrophenyl)azetidin-3-yl]acetamide

Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl)-azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).

1-(4-Nitrophenyl)azetidin-3-ylamine

tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+).

tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate

tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 293.33 (C14H19N3O4); MS (ESI): 294 (M+H+).

Example 38 tert-Butyl [1-(4-{[4-(4-Chlorophenyl)piperidin-1-carbonyl]amino}-phenyl)azetidin-3-yl]methylcarbamate

tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 499.06 (C27H35ClN4O3; MS (ESI): 499 (M+H+).

tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate

tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate was hydrogenated by method B. This resulted in the product with the molecular weight of 277.37 (C15H23N3O2); MS (ESI): 278 (M+H+).

tert-Butyl methyl-[1-(4-nitrophenyl)azetidin-3-yl]carbamate

tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).

Example 39 4-(4-Chlorophenyl)piperidin-1-carboxylic acid [4-(3-methylaminoazetidin-1-yl)phenyl]amide

tert-Butyl [1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}-phenyl)azetidin-3-yl]methylcarbamate was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 398.94 (C22H27ClN4O); MS (ESI): 399 (M+H+).

Example 40 N-Methyl-N-[1-(4-{3-[4-(pyridin-3-yloxy)phenyl]ureido}phenyl)pyrrolidin-3-yl]acetamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(pyridin-3-yloxy)phenylamine by method A. This resulted in the product with the molecular weight of 445.53 (C25H27N5O3); MS (ESI): 446 (M+H+).

Example 41 N-Methyl-N-(1-{4-[3-(4-piperidin-1-ylphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-piperidin-1-ylphenylamine by method A. This resulted in the product with the molecular weight of 435.57 (C25H33N5O2); MS (ESI): 436 (M+H+).

Example 42 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-phenoxybenzamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxybenzoic acid by method E. This resulted in the product with the molecular weight of 429.52 (C26H27N3O3); MS (ESI): 430 (M+H+).

Example 43 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxybenzamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 409.53 (C24H31N3O3); MS (ESI): 410 (M+H+).

Example 44 4-(4-Chlorophenyl)cyclohexanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-(4-chlorophenyl)cyclohexanecarboxylic acid by method E. This resulted in the product with the molecular weight of 454.02 (C26H32ClN3O2); MS (ESI): 454 (M+H+).

Example 45 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-3-(4-isopropylphenyl)-acrylamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 3-(4-isopropylphenyl)acrylic acid by method E. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).

Example 46 Tetrahydrofuran-2-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with tetrahydrofuran-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 492.62 (C28H36N4O4); MS (ESI): 493 (M+H+).

Example 47 1-Acetylpyrrolidin-2-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 1-acetylpyrrolidine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 533.68 (C30H39N5O4); MS (ESI): 534 (M+H+).

Example 48 5-Oxopyrrolidine-2-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 5-oxo-pyrrolidine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 505.62 (C28H35N5O4); MS (ESI): 506 (M+H+).

Example 49 2-Oxothiazolidine-4-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 523.66 (C27H33N5O4S); MS (ESI): 524 (M+H+).

Example 50 (R)-1-Methylpiperidine-3-carboxylic acid {1-[4-(4-cyclohexylbenzoyl-amino)phenyl]pyrrolidin-3-yl}methylamide

(R)4-Cyclohexyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with 1-methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 502.71 (C31H42N4O2); MS (ESI): 503 (M+H+).

Example 51 N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide

N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then 6-cyclopentyloxypyridin-3-ylamine by method A. This resulted in the product with the molecular weight of 437.55 (C24H31N5O3); MS (ESI): 438 (M+H+).

6-Cyclopentyloxypyridin-3-ylamine

A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 80° C. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N20); MS (ESI): 179 (M+H+).

Example 52 1-(6-Cyclopentyloxypyridin-3-yl)-3-[4-(3-methylaminopyrrolidin-1-yl)-phenyl]urea

N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was treated with sodium hydroxide solution by method D. This resulted in the product with the molecular weight of 395.51 (C22H29N5O2); MS (ESI): 395 (M+H+).

Example 53 4′-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4′-fluorobiphenyl-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 431.51 (C26H26FN3O2); MS (ESI): 432 (M+H+).

Example 54 4′-Trifluoromethylbiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4′-trifluoromethylbiphenyl-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 481.52 (C27H26F3N3O2); MS (ESI): 482 (M+H+).

Examples 55-103

1-(4-Phenoxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 2.

Examples 104-144

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 3.

Examples 145-185

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with various carboxylic acids by method E. The products are compiled in table 4.

Examples 186-234

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with various amines by method A. The products are compiled in table 5.

TABLE 2 Molecu- Ex. Molecular lar No. Structure Name formula weight M + H+ 55

Cyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl)pyrrolidin-3-yl)amide C28H30N4O3 470.58 471 56

3,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)butyramide C29H34N4O3 486.62 487 57

2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)butyramide C29H34N4O3 486.62 487 58

N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)benzamide C31H30N4O3 506.61 507 59

(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-3-phenylacrylamide C33H32N4O3 532.65 533 60

2-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C31H36N4O3 512.66 513 61

Cyclohexanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H36N4O3 512.66 513 62

N-Methyl-2-methylsulfanyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide C27H30N4O3S 490.63 491 63

N-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide C27H30N4O4 474.56 475 64

2-Oxothiazolidine-4-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C28H29N5O4S 531.64 532 65

4-Fluoro-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)benzamide C31H29FN4O3 524.60 525 66

Pyridine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C30H29N5O3 507.60 508 67

2-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C28H31N5O4 501.59 502 68

2,2,3,3-Tetramethylcyclopropanecarboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide C32H38N4O3 526.68 527 69

3,5-Dimethylisoxazole-4-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C30H31N5O4 525.61 526 70

2-Ethoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)acetamide C28H32N4O4 488.59 489 71

3-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)propionamide C28H32N4O4 488.59 489 72

2,2,N-Trimethyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)butyramide C30H36N4O3 500.65 501 73

1-Methylcyclopropanecarboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide C29H32N4O3 484.60 485 74

Cyclobutanecarboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H32N4O3 484.60 485 75

N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)isonicotinamide C30H29N5O3 507.60 508 76

Pyrazine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N6O3 508.58 509 77

5-Oxopyrrolidine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H31N5O4 513.60 514 78

Thiophene-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N4O3S 512.64 513 79

Furan-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N4O4 496.57 497 80

N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)nicotinamide C30H29N5O3 507.60 508 81

4-Cyano-N-methyl-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)benzamide C32H29N5O3 531.62 532 82

1-Methyl-1H-pyrrole-2-carboxylicacid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C30H31N5O3 509.61 510 83

3-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide C32H38N4O3 526.68 527 84

N,N,N′-Trimethyl-N′-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)succinamide C30H35N5O4 529.64 530 85

3-Phenylpropynoic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C33H30N4O3 530.63 531 86

(1R,4S)-Bicyclo[2.2.1]heptane-2-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide C32H36N4O3 524.67 525 87

[1,2,3]Thiadiazol-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C27H26N6O3S 514.61 515 88

Isoxazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C28H27N5O4 497.56 498 89

2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)benzamide C32H32N4O3 520.64 521 90

2-Methanesulfonyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-aceta-mide C27H30N4O5S 522.63 523 91

(E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-3-pyridin-3-ylacrylamide C32H31N5O3 533.64 534 92

4,4,4-Trifluoro-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)butyramide C28H29F3N4O3 526.56 527 93

2-Dimethylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C28H33N5O3 487.61 488 94

3-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide C29H33N5O4 515.62 516 95

Tetrahydrofuran-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-amide C29H32N4O4 500.60 501 96

N-Methyl-2-(3-methylisoxazol-5-yl)-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-ace-tamide C30H31N5O4 525.61 526 97

(S)-1-Acetylpyrrolidine-2-carboxylicacid methyl-(1-{4-[3-(4-phe-noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H35N5O4 541.66 542 98

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidine-3-yl)amide C28H28N6O3S 528.64 529 99

1,5-Dimethyl-1H-pyrazole-3-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)amide C30H32N6O3 524.63 525 100

5-Methylhexanoic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H38N4O3 514.67 515 101

Tetrahydropyran-4-carboxylic acid methyl-(1-{4-[3-(4-phe-noxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-amide C30H34N4O4 514.63 515 102

N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)-2-piperi-din-1ylacetamide C31H37N5O3 527.67 528 103

1,3-Dimethyl-1H-pyrazole-4-carboxylic acidmethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)amide C30H32N6O3 524.63 525

TABLE 3 Molecu- Ex. Molecular lar No. Structure Name formula weight M + H+ 104

Benzyl(S)-5-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxo-imidazolidine-1-carboxylate C35H40N6O6 640.75 641 105

Benzyl(R)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate C36H43N5O5 625.77 626 106

N-(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe-nyl]pyrrolidin-3-yl)-3-dimethylamino-N-methyl-benzamide C32H39N5O3 541.70 542 107

Benzyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-5-oxo-pyrrolidine-1-carboxylate C36H41N5O6 639.76 640 108

tert-Butyl 3-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methyl-carbamoyl]piperidine-1-carboxylate C34H47N5O5 605.78 606 109

Benzyl 5-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxo-imidazolidine-1-carboxylate C35H40N6O6 640.75 641 110

1-Methylpiperidine-3-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide C30H41N5O3 519.69 520 111

2,6-Dioxohexahydropyrimidine-4-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide C28H34N6O5 534.62 535 112

2-Methyl-5-oxopyrrolidine-2-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide C29H37N5O4 519.65 520 113

tert-Butyl 4-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-thia-zolidine-3-carboxylate C32H43N5O5S 609.79 610 114

Benzyl(2S,4R)-4-tert-butoxy-2-[(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-carbamoyl]pyrrolidine-1-carboxylate C40H51N5O6 697.88 698 115

N-(1-{4-[3-(4-Cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)-3-(2,5-di-oxopyrrolidin-1-yl)-N-methyl-5-tri-fluoromethylbenzamide C35H36F3N5O5 663.70 664 116

tert-Butyl-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-mor-pholine-4-carboxylate C33H45N5O6 607.76 608 117

(R)-1-(Toluene-4-sulfonyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide C35H43N5O5S 645.83 646 118

{(3aS,6aS)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-hexa-hydrocyclopenta[b]pyrrol-1-yl}oxoacetic acidmethyl ester C34H43N5O6 617.75 618 119

(S)-1-(2,2,2,-Trifluoroacetyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylamide C30H36F3N5O4 587.65 588 120

2-Chloro-N-{[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methyl-carbamoyl]-methyl}benzamide C32H36ClN5O4 590.13 590 121

N-{1-[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]ethyl}-4-methyl-benzamide C34H41N5O4 583.74 584 122

N-{[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]methyl}-3,3-di-methylbutyramide C31H43N5O4 549.72 550 123

N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-2-(1H-imidazol-4-yl)-N-methyl-acetamide C28H34N6O3 502.62 503 124

Benzyl 3-[(1-(4-[3-(4-cyclo-pentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidine-1-car-boxylate C37H45N5O5 639.80 640 125

1-(Furan-2-carbonyl)piperidine-3-carboxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide C34H41N5O5 599.74 600 126

(E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-2-yl-acryl-amide C31H35N5O3 525.66 526 127

(E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-4-yl-acryl-amide C31H35N5O3 525.66 526 128

N-(1-{4-[3-(4-Cyclopentyl-oxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)-N-methyl-2-pyridin-3-ylacetamide C30H35N5O3 513.65 514 129

4-Methyl-3-oxo-3,4-dihy-dro-2H-benzo[1,4]thiazine-6-car-boxylic acid(1-{4-[3-(4-cyclopentyloxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methylamide C33H37N5O4S 599.76 600 130

Benzyl 2-[(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]-phe-nyl}pyrrolidin-3-yl)methylcarbamoyl]piperidin-1-car-boxylate C37H45N5O5 639.80 640 131

Benzyl(S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pipe-ridin-1-carboxylate C36H43N5O5 625.77 626 132

(R)-1-Acetylpyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide C30H39N5O4 533.68 534 133

(S)-1-((E)-3-Furan-2-ylacryloyl)pyrrolidine-2-car-boxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide C35H41N5O5 611.75 612 134

1-(2,2-Dimethylpropionyl)pyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide C33H45N5O4 575.76 576 135

(trans)-1-Methyl-5-oxo-2-py-ridin-3-ylpyrrolidine-3-car-boxylic acid(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylamide C34H40N6O4 596.74 597 136

(S)-1-Benzylpyrrolidine-2-carboxylicacid (1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyr-rolidin-3-yl)methyl-amide C35H43N5O3 581.76 582 137

Isobutyl 2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate C33H45N5O5 591.76 592 138

Allyl (S)-2-[(1-{4-[3-(4-cyclopentyloxyphenyl)-urei-do]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyr-rolidine-1-carboxylate C32H41N5O5 575.71 576 139

2-Oxoimidazolidine-4-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth-ylamide C27H34N6O4 506.61 507 140

(R)-5-Oxopyrrolidine-2-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)meth-ylamide C28H35N5O4 505.62 506 141

1-Methyl-5-oxopyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide C29H37N5O4 519.65 520 142

1-Benzyl-5-oxopyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidine-3-yl)methylamide C35H41N5O4 595.75 596 143

5-Oxo-1-phenylpyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclo-pentyloxyphenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide C34H39N5O4 581.72 582 144

5-Oxo-1-p-tolylpyrrolidine-3-carboxylicacid(1-{4-[3-(4-cyclopentyloxy-phenyl)ureido]phenyl}-pyr-rolidin-3-yl)methylamide C35H41N5O4 595.75 596

TABLE 4 Ex. No. Structure Name Molecular formula Molecular weight M + H+ 145

(E)-N-{4-[3-(Acetylmethylamin-o)pyrrolidin-1-yl]-phenyl}-3-(5,6-dimethylbenzooxazol-2-yl)-a-crylamide C25H28N4O3 432.53 433 146

4′-Ethylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C28H31N3O2 441.58 442 147

4′-Propylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C29H33N3O2 455.61 456 148

2′-Fluorobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C26H26FN3O2 431.51 432 149

4′-Cyanobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C27H26N4O2 438.53 439 150

4′-Bromobiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C26H26BrN3O2 492.42 492 151

4′-Ethoxybiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C28H31N3O3 457.58 458 152

3′,4′-Dichlorobiphenyl-4-car-boxylic acid {4-[3-(acetylme-thylamino)pyrrolidin-1-yl]-phenyl}amide C26H25Cl2N3O2 482.41 482 153

2-Ethylbiphenyl-4-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C28H31N3O2 441.58 442 154

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-benzenesulfonylbenzamide C26H27N3O4S 477.59 478 155

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-cyclopentyloxybenzamide C25H31N3O3 421.54 422 156

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)-3-nitro-benzamide C26H25ClN4O5 508.97 509 157

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-fluorophenoxy)benzamide C26H26FN3O3 447.51 448 158

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)benzamide C26H26ClN3O3 463.97 464 159

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-cyclohexylbenzamide C26H33N3O2 419.57 420 160

1-(4-Nitrophenyl)piperidine-4-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide C25H31N5O4 465.56 466 161

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-3-phenoxybenzamide C26H27N3O3 429.52 430 162

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-propoxybenzamide C23H29N3O3 395.51 396 163

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(cyclohex-2-enyloxy)-benzamide C26H31N3O3 433.56 434 164

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-(3-methylbutoxy)benzamide C25H33N3O3 423.56 424 165

N-{4-[3-(Acetylmethyla-mino)pyrrolidin-1-yl]phenyl}-4-isobutoxybenzamide C24H31N3O3 409.53 410 166

5-(4-Chlorophenyl)furan-2-carboxylic acid {4-[3-(ace-tylmethylamino)pyrrolidin-1-yl]phenyl}amide C24H24ClN3O3 437.93 438 167

5-(4-Methoxyphenyl)thiophene-2-carboxylic acid {4-[3-(ace-tylmethylamino)pyrrolidin-1-yl]-phenyl}amide C25H27N3O3S 449.58 450 168

5-(4-Chloro-2-nitrophenyl)-furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrroli-din-1-yl]phenyl}amide C24H23ClN4O5 482.93 483 169

5-(4-Methyl-2-nitrophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrroli-din-1-yl]phenyl}-amide C25H26N4O5 462.51 463 170

5-(4-Fluorophenyl)thiophene-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C24H24FN3O2S 437.54 438 171

5-(2,4-Dichlorophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C24H23Cl2N3O3 472.38 472 172

4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-carboxylicacid{ 4-[ 3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide C25H25F3N4O2S 502.56 503 173

2-(4-Chlorophenyl)-4-methyl-thiazole-5-carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide C24H25ClN4O2S 469.01 469 174

5-Benzyloxy-1H-indole-2-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide C29H30N4O3 482.59 483 175

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-4-benzyloxybenzamide C27H29N3O3 443.55 444 176

5-Phenylethynylfuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide C26H25N3O3 427.51 428 177

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-biphenyl-4-ylacetamide C27H29N3O2 427.55 428 178

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide C25H33N3O3 423.56 424 179

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-benzyloxyphenyl)acetamide C28H31N3O3 457.58 458 180

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-phenoxyphenyl)acetamide C27H29N3O3 443.55 444 181

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-benzyloxy-3-methoxy-phenyl)acetamide C29H33N3O4 487.60 488 182

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4′-fluorobiphenyl-4-yl)acetamide C27H28FN3O2 445.54 446 183

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-[4-(2,5-dimethylpyrrol-1-yl)phenyl]acetamide C27H32N4O2 444.58 445 184

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-isopropylphenoxy)-acetamide C24H31N3O3 409.53 410 185

N-{4-[3-(Acetylmethylamino)-pyrrolidin-1-yl]phenyl}-2-(4-ethylphenoxy)acetamide C23H29N3O3 395.51 396

TABLE 5 Ex. No. Structure Name Molecular formula Molecular weight M + H+ 186

N-Methyl-N-(1-{4-[3-(6-phe-noxypyridin-3-yl)ureido]phenyl}-pyrrolidin-3-yl)acetamide C25H27N5O3 445.53 446 187

N-[1-(4-{3-[4-(2-Chlorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide C26H27ClN4O3 478.98 479 188

N-[1-(4-{3-[4-(3-Chlorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide C26H27ClN4O3 478.98 479 189

N-Methyl-N-[1-{4-[3-(4-o-tolyloxyphenyl)ureido}-phenyl)-pyrrolidin-3-yl)acetamide C27H30N4O3 458.57 459 190

N-Methyl-N-[1-{4-[3-(4-m-tolyloxyphenyl)ureido}-phenyl)-pyrrolidin-3-yl)acetamide C27H30N4O3 458.57 459 191

N-[1-{4-{3-[4-(2-Fluorophen-oxy)phenyl)ureido}-phenyl)-pyrrolidin-3-yl)-N-methyl-acetamide C26H27FN4O3 462.53 463 192

N-{1-{4-[3-Biphenyl-4-yl-ureido}phenyl]pyrrolidin-3-yl}-N-methylacetamide C26H28N4O2 428.54 429 193

N-[1-(4-{3-[4-(2-Methoxyphe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]methyl-acetamide C27H30N4O4 474.56 475 194

N-(1-{4-[3-(4-Isobutoxyphenyl)-ureido}phenyl)pyrrolidin-3-yl]-N-methylacetamide C24H32N4O3 424.55 425 195

N-(1-{4-[3-(4-Cyclopentyloxy-phenyl)ureido}phenyl)pyrro-lidin-3-yl]-N-methylacet-amide C25H32N4O3 436.56 437 196

N-[1-(4-{3-[4-(4-Fluorophe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide C26H27FN4O3 462.53 463 197

N-[1-(4-{3-[4-(3-Methoxyphe-noxy)phenyl]ureido}-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide C27H30N4O4 474.56 475 198

4-(3-Acetylaminophenyl)piperi-dine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]-phenylamide C27H35N5O3 477.61 478 199

N-Methyl-N-(1-{4-[3-(5-phenyl-pyridin-2-yl)ureido]-phenyl}-pyrrolidin-3-yl)acetamide C25H27N5O2 429.53 430 200

N-(1-{4-[3-(2-Acetylamino-4-phenylsulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C28H31N5O3S 517.65 518 201

N-(1-{4-[3-(4′-Cyanobiphenyl-4-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C27H27N5O2 453.55 454 202

N-(1-{4-[3-(2-Methoxybiphenyl-4-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C27H30N4O3 458.57 459 203

4-(2-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyr-rolidin-1-yl]phenyl}amide C25H31ClN4O2 455.00 455 204

N-(1-{4-[3-(4-Benzene-sulfonyl-3-chlorophenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C26H27ClN4O4S 527.05 527 205

4-(4-Chlorophenyl)-4-hydroxy-piperidine-1-carboxylicacid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide C25H31ClN4O3 471.00 471 206

4-Phenylpiperidine-1-carboxylicacid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide C25H32N4O2 420.56 421 207

4-Cyano-4-phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide C26H31N5O2 445.57 446 208

4-Acetyl-4-phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide C27H34N4O3 462.60 463 209

4-(2-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C26H34N4O3 450.59 451 210

4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C25H31FN4O2 438.55 439 211

4-(3-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide C25H31FN4O2 438.55 439 212

4-(2-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrro-lidin-1-yl]phenyl}amide C25H31FN4O2 438.55 439 213

4-p-Tolylpiperidine-1-carboxylicacid {4-[3-(acetyl-methylamino)-pyrrolidin-1-yl]phenyl}amide C26H34N4O2 434.59 435 214

4-(4-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid{4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}-amide C26H31F3N4O2 488.56 489 215

4-(3-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid{4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}-amide C26H31F3N4O2 488.56 489 216

4-(2-Trifluoromethylphenyl)pi-peridine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H31F3N4O2 488.56 489 217

4-(4-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}-amide C26H34N4O3 450.59 451 218

4-(3-Methoxyphenyl)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}-amide C26H34N4O3 450.59 451 219

4-Naphthalen-2-ylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C29H34N4O2 470.62 471 220

Benzo[c]-1-oxa-8-aza-spiro-[4,5]decane-8-car {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C26H32N4O3 448.57 449 221

N-(1-{4-[3-(9-Ethyl-9H-carbazol-3-yl)ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide C28H31N5O2 469.59 470 222

N-(1-(4-{3-[4-(4-Chloro-phenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl)-N-methylacetamide C26H27ClN4O3 478.98 479 223

N-(1-{4-[3-(4-Benzylphenyl)-ureido]phenyl}-pyrrolidin-3-yl)-N-methylacetamide C27H30N4O2 442.57 443 224

N-Methyl-N-(1-{4-[3-(4-Pyri-din-4-ylmethylphenyl)-ureido]-phenyl}pyrrolidin-3-yl)aceta-mide C28H30F3N5O4 443.55 444 225

N-[1-(4-{3-[6-(2-Fluorophe-noxy)pyridin-3-yl]ureido}-phenyl}pyrrolidin-3-yl)-N-methylacetamide C25H26FN5O3 463.52 464 226

N-Methyl-N-(1-{4-[3-(4-phenyl-sulfanylphenyl)-ureido]phenyl}-pyrrolidin-3-yl)acetamide C26H28N4O2S 460.60 461 227

N-Methyl-N-[1-(4-{3-[4-(3-tri-fluoromethylphenoxy)-phenyl]-ureido}phenyl)pyrrolidin-3-yl]-acetamide C27H27F3N4O3 512.54 513 228

N-Methyl-N-[1-(4-{3-[6-(pyridin-2-ylsulfanyl)pyridin-3-yl]ureido}phenyl)pyrrolidin-3-yl]acetamide C26H27F3N6O4S 462.58 463 229

N-(1-{4-[3-(4-Butoxyphenyl)-ureido]phenyl}-pyrrolidin-3-yl)-N-methylacetamide C24H32N4O3 424.55 425 230

4-Benzylpiperidine-1-carboxylicacid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide C26H34N4O2 434.59 435 231

Benzo-8-azaspiro[4.5]decane-8-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C27H34N4O2 446.60 447 232

4-Benzofuran-3-ylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C27H32N4O3 460.58 461 233

4-p-Tolyloxypiperidine-1-car-boxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]-phenyl}amide C26H34N4O3 450.59 451 234

4-(2-Chlorophenoxy)piperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}-amide C25H31ClN4O3 471.00 471

Example 235 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-2-piperidin-1-yl-acetamide

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 519.69 (C30H41N5O3); MS (ESI): 520 (M+H+).

Example 236 1-Methylpiperidine-3-carboxylic acid {(R)-1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylamide

(R)-4-Cyclohexyl-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was reacted with 1-methylpiperidin-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 503.69 (C30H41N5O2); MS (ESI): 504 (M+H+).

Example 237 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)propionamide

Method H

Caesium carbonate (36 mg) and n-butyl bromide (15 mg) were added to a solution of N-{4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide (27 mg) in DMF (1 ml). After a reaction time of 2 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated, and the residue was crystallized from diethyl ether/methanol. This resulted in the product with the molecular weight of 437.59 (C26H35N3O3); MS (ESI): 438 (M+H+).

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 2-(4-hydroxyphenyl)propionic acid by method I. This resulted in the product with the molecular weight of 381.48 (C22H27N3O3); MS (ESI): 382 (M+H+).

Example 238 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-isobutoxyphenyl)acetamide

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide was reacted with isobutyl bromide by method H. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide

Method I

4-Hydroxyphenylacetic acid (305 mg), 1-hydroxybenzotriazole (300 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg) in DMF (5 ml) were stirred with N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (470 mg) at room temperature for 3 hours. Water was then added to the mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).

Example 239 (R)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxyphenylacetic acid by method E. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).

Example 240 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-cyclopropylmethoxyphenyl)propionamide

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclopropane by method H. This resulted in the product with the molecular weight of 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).

Example 241 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-cyclobutylmethoxyphenyl)propionamide

N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane by method H. This resulted in a product with the molecular weight 449.60 (C27H35N3O3); MS (ESI): 450 (M+H+).

Example 242 1-(4-Methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid by method E. This resulted in the product with the molecular weight of 407.52 (C24H29N3O3); MS (ESI): 408 (M+H+).

Example 243 1-(4-Butoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide

1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60, (C27H35N3O3); MS(ESI): 450 (M+H+).

1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) in dichloromethane (5.5 ml) at 0° C. After a reaction time of 12 hours at room temperature, water was added to the mixture, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 8:1:1 with addition of 0.1% triethylamine). This resulted in the product with the molecular weight of 393.49 (C23H27N3O3); MS(ESI): 394 (M+H+).

Example 244 (R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-N-methylamide

(R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted in the product with the molecular weight of 452.58 (C26H33FN4O2); MS (ESI): 453 (M+H+).

Example 245 5-2-[(2-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

Method J

Firstly diisopropylamine (14.9 mg) and then a solution of 5-bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (50.0 mg) and 1-ethynyl-2-fluorobenzene (17.7 mg) in dioxane (0.5 ml) and DMF (0.2 ml) were added under inert conditions to a suspension of palladium bis(tri-tert-butylphosphine) dichloride (3.8 mg) and copper(I) iodide (0.9 mg) in DMF (0.5 ml). After a reaction time of 12 hours at room temperature, the mixture was diluted with ethyl acetate and filtered through silica gel, and the filtrate was concentrated and purified by preparative HPLC. This resulted in the product with the molecular weight of 445.18 (C26H24FN3O3); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate.

5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 5-bromo-2-furancarboxylic acid by method E. This resulted in the product with the molecular weight of 406.28 (C18H20BrN3O3); MS(ESI): 407 (M+H+).

Example 246 5-2-[(4-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide was reacted with 1-ethynyl-4-fluorobenzene by method J. This resulted in the product with the molecular weight of 445.18 (C26H24FN3O3); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate.

Example 247 5-2-[(2-Chlorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide was reacted with 1-ethynyl-2-chlorobenzene by method J. This resulted in the product with the molecular weight of 461.15 (C26H24ClN3O3); MS(ESI): 462 (M+H+) as hydrotrifluoroacetate.

Example 248 R-4-Butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methylpropyl)methylamino]-pyrrolidin-1-yl}-phenyl)benzamide

A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide (0.03 g) and isobutylene oxide in ethanol (5 ml) were heated under reflux for 3 hours. It was then concentrated in vacuo. This resulted in the product with the molecular weight of 457.59 (C26H36FN3O3); MS (ESI): 458 (M+H+).

Example 249 R-4-Butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3-methylbutyl)methylamino]pyrrolidin-1-yl}-phenyl)-N-methylbenzamide

A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide (0.03 g), triethylamine (0.02 g) and 4-bromo-2-methylbutan-2-ol (0.03 g) in DMF (2 ml) was heated at 80° C. for 16 hours. After cooling, ethyl acetate (100 ml) was added, the mixture was washed with water (2×50 ml), and the organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.62 (C27H38FN3O3); MS (ESI): 472 (M+H+).

4-Bromo-2-methylbutan-2-ol

Methylmagnesium bromide (3M in diethyl ether, 46 ml) was added to a solution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 ml) at room temperature under argon. During this, the mixture was kept at above 20° C. and below 35° C. After 2 hours, the mixture was poured into a saturated ammonium chloride solution. This was followed by extraction with diethyl ether, drying with sodium sulfate, filtration and concentration. This resulted in the desired product.

Example 250 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)-pyridin-3-yl]benzamide

Method K

A solution of (R)-N-[6-(3-aminopyrrolidin-1-yl)pyridin-3-yl]-4-butoxybenzamide (0.065 g) in methanol (2 ml) was mixed with glacial acetic acid (0.11 ml) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.19 g). Then sodium cyanoborohydride (0.051 g) was added and the mixture was heated under reflux for 16 hours. The mixture was then filtered, concentrated, taken up in dichloromethane, washed with sodium hydroxide (2N; 20 ml) and sodium chloride solution (20 ml), dried with magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 434.59 (C26H34N4O2); MS (ESI): 435 (M+H+).

Example 251 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yl]-N-methylbenzamide

(R)-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was methylated by method F. This resulted in the product with the molecular weight of 448.61 (C27H36N4O2); MS (ESI): 449 (M+H+).

Example 252 R-4-Butoxy-N-{6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyridin-3-yl}benzamide

(R)-4-Butoxy-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was cyclopropylated by method K. This resulted in the product with the molecular weight of 408.551 (C24H32N4O2); MS (ESI): 409 (M+H+).

Example 253 tert-Butyl {1-[4-(2-amino-4-butoxybenzoylamino)-3-fluorophenyl]pyrrolidin-3-yl}methylcarbamate

tert-Butyl [1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed by hydrogenation. This resulted in the product with the molecular weight of 500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+).

4-Butoxy-2-nitrobenzoic acid

A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110° C. for 4 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (3×50 ml), dried with sodium sulfate, filtered and concentrated in vacuo. The residue (2.2 g) was added dropwise at −10° C. to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at −10° C. under argon and then stirred for 20 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (10N; 100 ml) and extracted with dichloromethane, and the organic phase was dried over sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 239.23 (C11H13NO5); MS (ESI): 240 (M+H+).

Example 254 N-{4-[3-(7-Azabicyclo[2.2.1]hept-7-yl)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide

Method L

A mixture of N-[4-(3-bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide (100 mg), potassium carbonate (60 mg), 7-azabicyclo[2.2.1]heptane (44 mg) and DMF (2 ml) was kept at 50° C. for 6 hours. The mixture was diluted with water and extracted with ethyl acetate.

The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.65 (C30H37N3O2); MS (ESI): 472 (M+H+).

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide

N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. The same amount of sodium hydroxide solution was then added, and stirring was continued for 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). This resulted in the product with the molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+).

N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide

4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was ethylated by method F and hydrogenated by method B. This resulted in the product with the molecular weight of 308.43 (C20H24N2O); MS (ESI): 309 (M+H+).

Example 255 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxopyrrolidin-1-yl)phenyl]benzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).

Example 256 4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1-ylpyrrolidin-1-yl)phenyl]benzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with piperidine by method L. This resulted in the product with the molecular weight of 459.64 (C29H37N3O2); MS (ESI): 460 (M+H+).

Example 257 4-Cyclohexyl-N-methyl-N-[4-(2′-oxo[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with pyrrolidine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).

Example 258 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with methylamine by method L. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).

Example 259 4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxopyrrolidin-1-yl)phenyl]-N-methylbenzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).

Example 260 4-Cyclohexyl-N-{4-[3-(cyclopropylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-N-methylbenzamide

N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).

Example 261 N-{4-[3-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methyl-benzamide

4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (52 mg) was mixed with pyridine (0.5 ml) and acetic anhydride (130 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).

Example 262 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide

tert-Butanol (8 ml), triethylamine (350 mg) and finally diphenylphosphoryl azide (1.18 g) were added to 1-{4-[(4-cyclohexylbenzoyl)methylamino]phenyl}-5-oxopyrrolidin-3-carboxylic acid (1.5 g), and the mixture was heated at 95° C. for 48 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was reacted further by method G. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).

1-{4-[(4-Cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidine-3-carboxylic acid

N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) was heated with itaconic acid (1.27 g) at 100° C. for 3 hours. Purification took place by filtration through silica gel (mobile phase ethyl acetate/methanol 5:1). This resulted in the product with the molecular weight of 420.51 (C25H28N2O4); MS (ESI): 421 (M+H+).

Example 263 N-{4-[4-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide

4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).

Example 264 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)propylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

Method F-a

tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate (50 mg), cesium carbonate (249 mg), potassium iodide (17 mg), N-methylpyrrolidone (1.5 ml) and propyl iodide (40 mg) were stirred at 60° C. for 5 hours. If conversion was incomplete, the mixture was heated to 100° C. and, after addition of further propyl iodide (40 mg), heated at 140° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and sodium bicarbonate solution, dried over Chromabond XTR and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 520.72 (C31H44N4O3); MS (ESI): 521 (M+H+).

Example 265 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(1-ethylpropyl)amino]pyridin-2-yl}pyrrolidin-3-yl)-methylcarbamate

tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 2-ethylbutyl bromide by method F-a. This resulted in the product with the molecular weight of 548.78 (C33H48N4O3); MS (ESI): 549 (M+H+).

Example 266 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(3-methylbut-2-enyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide by method F-a. This resulted in the product with the molecular weight of 546.76 (C33H46N4O3); MS (ESI): 547 (M+H+).

Example 267 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)methylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate

tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with methyl iodide by method F-a. This resulted in the product with the molecular weight of 492.67 (C29H40N4O3); MS (ESI): 493 (M+H+).

The following further compounds were obtained by method F-a from tert-butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate and the appropriate alkylating agent:

-   tert-Butyl     (1-{5-[sec-butyl-(4-cyclohexylbenzoyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate -   tert-Butyl     (1-{5-[(4-cyclohexylbenzoyl)isopropylamino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate -   tert-Butyl     (1-{5-[(4-cyclohexylbenzoyl)prop-2-inylamino]pyridin-2-yl}pyrrolidin-3-yl)-methylcarbamate

Example 268 5-p-Tolylethinylfuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)₂Cl₂ and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.

5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate.

Examples 269-273 were prepared analogously:

Molecular Molecular Ex. No. Structure formula weight M+H+ 269

C26H27N303 429.21 430 270

C25H23F2N3O2 435.18 436 271

C26H27N3O3 429.21 430 272

C25H24FN3O2 417.19 418 273

C25H24CIN3O2 433.16 434

Example 274 (R)-4′-Fluorobiphenyl-4-carboxylic acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide

Method M

(R)-4′-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]-amide (390 mg) dissolved in formic acid (230 mg) was mixed with formaldehyde solution (37% aq.; 0.4 ml) and the mixture was heated at 80° C. for 3 hours. The cooled reaction solution was concentrated and partitioned between ethyl acetate and a saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+).

Example 275 1-(4-Fluorophenyl)piperidine-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

Method E-a

A mixture of 0.048 g of 1-(4-fluorophenyl)piperidine-4-carboxylic acid and 0.5 ml of SOCl₂ and one drop of DMF were stirred at room temperature for 2 hours. The excess SOCl₂ was then removed in vacuo. The residue was dissolved in 0.4 ml of DMF, and 0.033 ml of triethylamine and 0.048 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide were added. The solution was stirred at room temperature overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 438.20 (C25H31FN4O2); MS (ESI): 439 (M+H+) as hydrotrifluoroacetate.

1-(4-Fluorophenyl)piperidine-4-carboxylic acid

0.875 g of 4-bromofluorobenzene, 0.016 g of Pd(dba)3*CHCl3, 0.022 g 2-(dicyclohexylphosphino)biphenyl and 2.28 g of cesium carbonate were put in a heat-dried and argon-flushed flask, and 0.943 g of ethyl 4-piperidinecarboxylate in 5 ml of degassed toluene was added. The solution was heated at 100° C. overnight. The mixture was cooled and then concentrated in vacuo. The residue was taken up in ethyl acetate/water. The organic phase was washed with 10% NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC.

4.4 ml of a 2N potassium hydroxide solution were added to a solution of 1.1 g of ethyl 1-(4-fluorophenyl)piperidine-4-carboxylate in 100 ml of methanol. The mixture was stirred at room temperature overnight. The pH was then adjusted to 6 with 5% hydrochloric acid, and the solution was concentrated in vacuo. The residue was purified by preparative HPLC.

Example 276 4-Phenoxycyclohexanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide

0.251 g of PyBOP and 0.135 ml of triethylamine were added to a solution of 0.106 g of 4-phenoxycyclohexanecarboxylic acid and 0.113 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 9 ml of DMF at 0° C. After 10 minutes, the solution was allowed to reach room temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% citric acid and 10% NaHCO3 solution and dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 435.25 (C26H33N3O3), MS: 436 (M+H+).

4-Phenoxycyclohexanecarboxylic acid

0.63 g of p-toluenesulfonyl chloride was added to a solution of 0.522 g of ethyl 4-hydroxycyclohexanecarboxylate in 5.0 ml of pyridine. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting solid was taken up in water and ethyl acetate, and the organic phase was washed three times with 2N hydrochloric acid and once with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting product was employed without further purification in the next step. The resulting product (0.55 g) was dissolved in 11.2 ml of DMF, and 0.159 g of phenol and 0.549 g of cesium carbonate were added. The solution was then heated at 80° C. for 6 hours. After cooling, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: ethyl acetate/n-heptane 1:1). The desired product was obtained. Molecular weight 248.32 (C15H20O3), MS: 249 (M+H+).

0.06 ml of 2N potassium hydroxide solution was added to a solution of 0.12 g of ethyl 4-phenoxycyclohexanecarboxylate in 8 ml of water/THF (1:1). The solution was heated at 60° C. for 3 hours. Ethyl acetate and 10% citric acid were added to the mixture. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The resulting compound was employed without further purification in the next stage.

Example 277 N-[4-(3-Cyclohexylaminopyrrolidin-1-yl)phenyl]-4-isobutoxybenzamide

Method N

(4-Isobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide (50 mg) in methanol (2 ml) was mixed with aminocyclohexane (28 mg) and glacial acetic acid (10 mg), and a solution of sodium cyanoborohydride (1M in toluene; 0.17 ml) was added. After 8 hours, the reaction solution was concentrated and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the. product with the molecular weight of 435.61 (C27H37N3O2); MS (ESI): 436 (M+H+).

4-Isobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide

4-Isobutoxybenzoic acid was reacted with 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)phenylamine by method E-a. The resulting amide (0.25 g) in acetone (10 ml) was mixed with para-toluene sulfonic acid (monohydrate, 109 mg), and the mixture was boiled under reflux for 8 hours. After adding triethylamine (0.5 ml), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+).

4-Butoxy-N-[4-(3-oxopyrrolidin-1-yl)-phenyl]benzamide was obtained using 4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acid and 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine initially resulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]benzamide which, after methylation by method F and treatment with para-toluenesulfonic acid as described above, afforded 4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1-yl)phenyl]benzamide.

4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)phenylamine

Trimethylchlorosilane (9.3 g) was slowly added to a solution of 1-benzyl-3-pyrrolidinone (5.0 g) in dichloromethane (30 ml) and ethylene glycol (2.67 g). After 18 hours, the mixture was poured into sodium hydroxide solution (1N). The organic phase was separated off, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (30 ml) and ammonium formate (5.2 g) and palladium hydroxide (10% on carbon, 300 mg) were added. The mixture was boiled under reflux for 8 hours, filtered and concentrated. The residue was reacted with 4-fluoronitrobenzene by method C. Hydrogenation was finally carried out by method B. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).

4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine was obtained analogously using 3,4-difluoronitrobenzene.

Example 278 (R)-4-(4-Chlorophenyl)piperidin-1-carboxylic acid {4-[3-(methylpyrimidin-2-yl-amino)pyrrolidin-1-yl]-phenyl}amide

(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) in N-methylpyrrolidone (3 ml) at 100° C. for 4 hours. The reaction solution was then partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.04 (C27H31ClN6O); MS (ESI): 491 (M+H+).

Example 279 tert-Butyl [1-(4-{[5-(2-fluorophenyl)furan-2-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate

Method O

Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate (252 mg) in degassed toluene (4 ml) under argon in a 10 ml two-necked flask and stirred at room temperature for 10 minutes. Then a solution of 2-fluorobenzeneboronic acid (73 mg in 1 ml of ethanol) and 0.35 ml of 2M sodium carbonate solution were added, and the mixture was stirred at 100° C. for 24 hours.

Then water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture, the organic phase was separated off, and the aqueous phase was extracted 2× with ethyl acetate (10 ml). The combined organic phases were concentrated and the residue was purified by preparative HPLC. The desired product with the molecular weight of 479.56 (C27H30FN3O4); MS (ESI): 480 (M+H+) was obtained as hydrotrifluoroacetate. It is alternatively possible to use cesium carbonate as base and to heat the reaction at 150° C. in a microwave apparatus for 3 minutes.

-   tert-Butyl     (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate -   5-Bromofuran-2-carboxylic acid was reacted with tert-butyl     [1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This     resulted in the product with the molecular weight of 464.36     (C21H26BrN3O4); MS (ESI): 464 (M+H+).

The following compounds were prepared analogously:

-   5-Bromofuran-2-carboxylic acid     [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide -   tert-Butyl     (1-{4-[(5-bromothiophene-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate -   2-Bromothiazole-4-carboxylic acid     [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide -   4-Iodo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide -   (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide -   4-Bromo-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-3-fluorobenzamide

Example 280 (3R)-3′-Cyanobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]amide

Method O-b

0.002 mg of Pd(PPh3)4 were added to a solution of 0.022 g of (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide in 0.45 ml of degassed DMF and stirred at room temperature for 10 minutes. 0.035 ml of water, 0.021 g of K3PO4 and 0.008 g of 3-cyanophenylboronic acid were then added to the solution. The reaction solution was heated at 80° C. overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 428.20 (C26H25FlN4O); MS (ESI): 429 (M+H+) as hydrotrifluoroacetate.

Example 281 3,2′,4′-Trifluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

1-Bromo-2,4-difluorobenzene was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide by method O-b. This resulted in the product with the molecular weight of 439.19 (C25H24F3N3O); MS (ESI): 440 (M+H+) as hydrotrifluoroacetate.

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide

4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 371.18 (C19H23BFN3O3); MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.

Example 282 5-(2,4-Difluorophenyl)thiophen-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

1-Bromo-2,4-difluorobenzene was reacted with 2-boronic acid thiophen-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide by method O-b. This resulted in the product with molecular weight of 427.52 (C23H23F2N3OS); MS (ESI): 428 (M+H+) as hydrotrifluoroacetate.

2-Boronic acid thiophene-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

5-Carboxy-2-thiopheneboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 359.15 (C17H22BN3O3S); MS (ESI): 360 (M+H+) as hydrotrifluoroacetate.

Example 283 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4-fluorophenyl)nicotinamide

5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl [trifluoro-methanesulfonate was reacted with 4-fluorobenzeneboronic acid under the conditions of method O-b. (Heating at 140° C. in a microwave apparatus for 15 minutes). This resulted in the product with the molecular weight of 404.20 (C24H25FN4O); MS (ESI): 405 (M+H+) as hydrotrifluoroacetate.

5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate

A suspension of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-6-hydroxynicotinamide in 0.4 ml of DME was added to a solution of 0.084 ml of LDA solution (2M) in 0.4 ml of DME at 0° C. The mixture was stirred at 0° C. for 2 hours. A solution of 0.055 g of N-phenyltrifluoromethanesulfonimide in 0.2 ml of DME was then added to the mixture. The reaction solution was allowed to reach room temperature and was heated at 80° C. for 3 hours. After cooling, the solution was concentrated in vacuo. The residue was taken up in ethyl acetate/water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC.

N-[4-(3-Dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide

6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) as hydrotrifluoroacetate.

Example 284 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(2,4-difluorophenyl)nicotinamide

2,4-Difluorophenylboronic acid was reacted with 5-[4-(3-dimethylaminopyrrolidin-1-yl)-phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate by method O-b. This resulted in the product with the molecular weight of 422.00 (C24H24F2N4O); MS (ESI): 423 (M+H+) as hydrotrifluoroacetate.

Example 285 2′,4′-Difluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

2′,4′-Difluorobiphenyl-4-carboxylic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 421.20 (C25H25F2N3O); MS (ESI): 422 (M+H+) as hydrotrifluoroacetate.

2′,4′-Difluorobiphenyl-4-carboxylic acid

Method P

0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 g of ethyl 2′,4′-difluorobiphenyl-4-carboxylate in 1 ml THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was concentrated in vacuo, and the residue was purified by preparative HPLC.

Ethyl 2′,4′-difluorobiphenyl-4-carboxylate

0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl 4-iodobenzoate in 0.96 ml of degassed toluene and stirred at room temperature for 10 minutes. Then a solution of 0.047 g of 2,4-difluorophenylboronic acid in 0.114 ml of ethanol and 0.201 ml of a 2N Na2CO3 solution was added to the reaction solution. The solution was heated at 100° C. overnight. The reaction mixture was then concentrated in vacuo, and water/ethyl acetate were added to the residue. The aqueous phase was extracted three times with ethyl acetate and dried over sodium sulfate, and the solvent was removed in vacuo and purified by preparative HPLC.

Example 286 2′,4′-Difluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide

Method E-b

0.095 g of HATU, 0.068 g of HOBT and 0.035 ml of triethylamine were added to a solution of 0.047 g of 2′,4′-difluorobiphenyl-4-carboxylic acid and 0.058 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 2 ml of DMF at 0° C. After 10 minutes, the solution was allowed to reach room temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% NaHCO3 solution and water. The ethyl acetate phase was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 449.19 (C26H25F2N3O2), MS: 450 (M+H+).

Example 287 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-fluoro-4-(4-methylpiperidin-1-yl)-benzamide

3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid was reacted with [1-(4-aminophenyl)-pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 424.00 (C25H33FN4O); MS (ESI): 425 (M+H+) as hydrotrifluoroacetate.

3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid

Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate was treated with lithium hydroxide by method P. This resulted in the product with the molecular weight of 237.28 (C13H16FNO2); MS (ESI): 238 (M+H+).

Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate

0.076 g of potassium carbonate was added to a solution of 0.086 g of methyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of DMF. The reaction was heated at 60° C. for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.

Example 288 4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide

4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with N,N-dimethylglycine by method E. This resulted in the product with the molecular weight of 466.63 (C27H38N4O3); MS (ESI): 467 (M+H+).

(R)-4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide was obtained analogously.

Example 289 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxy-N-methylbenzamide

4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).

Example 290 4-Butyrylamino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

Method Q

4-Amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide (32 mg) in dichloromethane (2 ml) was mixed with potassium carbonate (50 mg) and butyryl chloride (11 mg). The mixture was filtered and concentrated after 12 hours. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 394.52 (C23H30N4O3); MS (ESI): 395 (M+H+).

An alternative possibility is to react 4-amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]benzamide with butyric acid by method E.

4-Amino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

4-tert-Butoxycarbonylaminobenzoic acid was reacted with 1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was treated by method G. This resulted in the product with the molecular weight of 324.43 (C19H24N4O); MS (ESI): 325 (M+H+).

Example 291 2-Phenylethynylthiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150° C. in a microwave apparatus for 3 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).

Example 292 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

Method O-a

5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) dissolved in toluene was mixed with 4-fluorophenylboronic acid (81 mg), POPD (15 mg) and cesium carbonate (2M aq.; 0.5 ml). The reaction was heated at 150° C. in a microwave apparatus for 10 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+).

5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (C18H21 ClN4O); MS (ESI): 345 (M+H+).

Example 293 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide

5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 4-methylphenylboronic acid by method O-a. This resulted in the product with the molecular weight of 400.53 (C25H28N4O); MS (ESI): 401 (M+H+).

Example 294 1-Benzenesulfonylpiperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+).

Example 295 1-(4-Fluorobenzenesulfonyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).

Example 296 1-(Butane-1-sulfonyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).

Example 297 5-(4-Butoxyphenylethynyl)furan-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide

Method J-a

5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynylbenzene (35 mg) in N,N-dimethylformamide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper (I) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 8 hours. The reaction was worked up by filtration through a syringe filter and concentrated, and the crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.6 (C29H33N3O3); MS (ESI): 472 (M+H+) as hydrotrifluoroacetate.

Example 298 6-Butoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide

Method H-a

A solution of 0.1 g of potassium hydroxide in 1 ml of DMSO was stirred at room temperature for 10 minutes and then 0.1 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide was added. The reaction solution was stirred for 10 minutes and then 0.084 g of 1-bromobutane was added. The mixture was stirred at room temperature overnight. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Example 299 6-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide

(Bromomethyl)cyclopropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 380.22 (C22H28N4O2); MS (ESI): 381 (M+H+) as hydrotrifluoroacetate.

Example 300 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-isobutoxynicotinamide

1-Bromo-2-methylpropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Example 301 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4-fluorophenoxy)nicotinamide

49 mg of potassium carbonate were added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide and 4-fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at 140° C. in a microwave apparatus for 90 minutes. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.

6-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide

6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21ClN4O); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.

The following examples were prepared analogously.

Molecular Molecular Ex. No. Structure formula weight M+H+ 302

C24H26N4O2 402.21 403 303

C24H25ClN4O2 436.17 437 304

C25H28N4O2 416.22 417

Example 305 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxybenzamide

Powdered molecular sieves (4 A), 0.01 g of copper acetate and 0.02 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide were added to a solution of 0.008 g of phenol in 0.5 ml of methylene chloride and stirred at 40° C. for 24 hours. The solvent was then removed in vacuo, the residue was taken up in water/ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 419.2 (C25H26FN3O2); MS (ESI): 420 (M+H+) as hydrotrifluoroacetate.

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide

4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 371.18 (C19H23BFN3O3); MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.

Example 306 4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A. This resulted in the product with the molecular weight of 440.40 (C24H37BN4O3); MS (ESI): 441 (M+H+)

Example 307 4-(2-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)

Example 308 4-(3-Methylsulfanylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromothioanisole by method O-a. This resulted in the product with the molecular weight of 436.62 (C25H32N4OS); MS (ESI): 437 (M+H+)

Example 309 4-(5-Chloropyridin-2-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

0.143 g of potassium carbonate was added to a solution of 0.19 g of 4-[4-(3-dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl acetate in 2 ml of DMF, and the solution was heated at 130° C. in a microwave apparatus for 15 minutes. The solution was then mixed with water and ethyl acetate, the aqueous phase was freeze-dried, and the residue was employed without further purification in the next stage.

Method R

A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of potassium carbonate in 0.8 ml of DMF was heated at 230° C. in a microwave apparatus for 30 minutes. The solution was filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 436.17 (C24H25ClN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

4-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]phenyl Acetate

4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) as hydrotrifluoroacetate.

Example 310 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-4-(5-fluoropyridin-2-yloxy)benzamide

2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.

Example 311 4-(6-Chloropyridin-3-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide

was obtained as by-product of the reaction in example 310. This resulted in the product with the molecular weight of 436.95 (C24H25ClN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

Example 312 5-Chloro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine (32 mg) and carbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), and the mixture was stirred for 3 hours. Triethylamine (63.4 μl) was added to a solution of 5-chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine (40.7 mg) in THF (1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was concentrated and the residue was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated. Contamination by the primary and/or secondary amine was removed by dissolving the residue in dichloromethane (1.5 ml) and adding the solution to a stirred suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 μl). After 3 hours, the resin was filtered off and washed several times with dichloromethane. The combined organic phases were concentrated. The residue was purified by chromatography (silica gel, mobile phase: ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 3%). This resulted in the product with the molecular weight of 425.97 (C23H28ClN5O); MS (ESI): 426 (M+H+).

5-Chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine

A solution of tert-butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 hours. This resulted in the product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+).

tert-Butyl 5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridine-1′-carbamate

A solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed with nitrogen; 4.5 ml) was added to a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carbamate (Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg), potassium carbonate (0.265 g) and Pd(dppf)Cl₂ (50 mg). The mixture was heated at 80° C. for 8 hours. After cooling, the mixture was diluted with dichloromethane and washed with sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), later heptane/ethyl acetate (5%)/dichloromethane (5%).

Example 313 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide

5-(2-Nitro-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was hydrogenated by method B. This resulted in the product with the molecular weight of 404.22 (C24H28N4O2); MS (ESI): 405 (M+H+).

Example 314 5-(2-Acetylamino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with acetyl chloride by method Q. This resulted in the product with the molecular weight of 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+).

Example 315 5-(2-Isobutyrylamino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with isobutyryl chloride by method Q. This resulted in the product with the molecular weight of 474.26 (C28H34N4O3); MS (ESI): 475 (M+H+).

Example 316 5′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]methylamide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-methylamide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at 160° C. for 15 minutes. o-Xylene (0.5 ml) was added and heating at 160° C. was continued for 2 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 442.01 (C24H32ClN5O); MS (ESI): 442 (M+H+).

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide

tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 330.48 (C19H30N4O); MS (ESI): 331 (M+H+).

Piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]-amide can be prepared analogously.

tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylcarbamoyl}-piperidine-1-carboxylate

A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thionyl chloride (0.21 ml) and, after 30 minutes, a solution of dimethyl[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml), DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16 hours, the mixture was diluted with dichloromethane, washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+).

tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin-1-carboxylate can be prepared analogously.

The following examples were prepared analogously.

Molecular Molecular Ex. No. Structure formula weight M+H+ 317

C25H30ClN5O 466.03 466 318

C24H30ClN5O3 471.99 472 319

C24H30FN5O3 455.54 456

Example 320 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160° C. for 2 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 160° C. for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 393.54(C23H31N5O); MS (ESI): 394 (M+H+).

The following examples were prepared analogously.

Molecular Molecular Ex. No. Structure formula weight M+H+ 321

C25H32ClN5O3 486.02 486 322

C24H30FN5O3 469.56 470

Example 323 5′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amid

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine (0.2 ml) were heated at 160° C. for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 427.98 (C23H30ClN5O); MS (ESI): 428 (M+H+).

Example 324 1-(4-Chloro-2-cyanophenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30ClN5O); MS (ESI): 452 (M+H+).

Example 325 1-(2-Acetylamino-4-chlorophenyl)piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]methylamide

Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 μl) was added. After one hour, further acetic anhydride (6 μl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36ClN5O2); MS (ESI): 498 (M+H+).

The following examples were prepared analogously.

Molecular Molecular Ex. No. Structure formula weight M+H+ 326

C27H36FN5O2 481.62 482 327

C26H34ClN5O2 484.05 484 328

C26H34FN5O3 467.59 468

Example 329 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-(4-phenylpiperidin-1-yl)acetamide

Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the mixture was kept at 65° C. for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).

It is alternatively possible to use potassium carbonate or pyridine as auxiliary bases, to add potassium iodide as catalyst, or to carry out the reaction at 150° C. in a microwave apparatus.

(R)-2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide

Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20ClN3O); MS (ESI): 282 (M+H+).

The following were obtained analogously:

-   N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-chloroacetamide -   2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide -   (R)-2-Chloro-N-[6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]acetamide

The following examples were prepared in analogy to the method given in example 329:

Molecular Molecular Ex. No. Structure formula weight M+H+ 330

C25H34N4O 406.58 407 331

C26H34N4O2 434.59 435 332

C26H33ClN4O2 469.03 469 333

C27H30N4O3 458.57 459 334

C25H29N5O2 431.54 432 335

C25H28ClN5O2 465.99 466 336

C26H33N5O3 463.59 464 337

C25H33ClN4O2 441.02 441 338

C25H34N4O2 422.58 423 339

C24H33N5O2 423.56 424

Example 340 (R)-4-Benzylpiperidine-1-carboxylic acid [6-(3-dimethylaminopyrrolidin-1-yl)pyridin-3-yl]-amide

(R)-6-(3-Dimethylaminopyrrolidin-1-yl)pyridin-3-ylamine was added to a solution of carbonyldiimidazole (53 mg) in DMF (0.5 ml) at 0° C. After 15 minutes, 4-benzylpiperidine (57 mg) was added and the mixture was heated at 90° C. for one hour. The cooled mixture was freed of volatile fractions. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 407.56 (C24H33N5O); MS (ESI): 408 (M+H+).

The following examples were prepared analogously:

Molecular Molecular Ex. No. Structure formula weight M+H+ 341

C24H31N5O2 421.55 422 342

C24H33N5O 407.56 408 343

C26H34N4O3 450.59 451 344

C25H31ClN4O2 455.00 455 345

C26H30N4O 414.56 415 346

C24H39N5O 413.61 414 347

C26H37N5O 435.62 436

Example 348 (R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-benzamide

(R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]benzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was alkylated with cyclopropylmethyl bromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).

The following examples were likewise obtained by method H:

Molecular Molecular Ex. No. Structure formula weight M+H+ 349

C26H34FN3O2 439.58 440 350

C25H32FN3O3 441.55 442 351

C24H30FN3O2 411.52 412

Example 352 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-(pyridin-2-yloxy)benzamide

(R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was reacted with 2-chloropyridine by method R. This resulted in the product with the molecular weight of 434.52 (C25H27N4O2); MS (ESI): 435 (M+H+).

Example 353-Example 507

Various pyrrolidinylanilines were reacted with diverse amines by method A. The resulting products are summarized in table 6.

Example 508-Example 1130

Various pyrrolidinylanilines were reacted with diverse acids by methods E. The resulting products are summarized in table 7.

Example 1131-Example 1232

Various (hetero)aryl halides were reacted with diverse boronic acids by methods O. The resulting products are summarized in table 8.

Example 1233-Example 1237

Various aryl halides were reacted with diverse acetylenes by methods J. The resulting products are summarized in table 9.

Example 1238-Example 1403

Various aminopyrrolidines and N-arylpyrrolidinones were reacted with diverse aldehydes, ketones and amines by method N. The resulting products are summarized in table 10.

Example 1404-Example 1423

Various aminopyrrolidines were reductively methylated with formaldehyde by method E. The resulting products are summarized in table 11.

Example 1424-Example 1443

Various amides were alkylated by method F. The resulting products are summarized in table 12.

Example 1444-Example 1618

Various tert-butyl carbamates were cleaved by method G. The resulting products were summarized in table 13.

TABLE 6 Molecular Monoisotopic Ex. No. Structure formula molecular wt. M+H⁺ 353

C25H31FN4O2 438.24 439 354

C25H30N4O4 450.23 451 355

C25H31ClN4O3 470.21 471 356

C26H30N4O2 430.24 431 357

C24H29ClN4O 424.20 425 358

C25H35N5O 421.28 422 359

C23H3OBrN5O 471.16 472 360

C24H34N4O 394.27 395 361

C26H28N4O3 444.22 445 362

C24H29N5O 403.24 404 363

C27H29N5OS 471.21 472 364

C26H30N4O2 430.24 431 365

C25H30N6O3 462.24 463 366

C22H25N5O2 391.20 392 367

C26H28N6O 440.23 441 368

C24H29FN4O 408.23 409 369

C26H30N4O3 446.23 447 370

C25H27ClN4O2 450.18 451 371

C25H27FN4O2 434.21 435 372

C26H30N4O2 430.24 431 373

C26H30N4O2 430.24 431 374

C26H30N4O3 446.23 447 375

C25H27ClN4O2 450.18 451 376

C23H32N4O2 396.25 397 377

C25H29N5O2 431.23 432 378

C24H27N5O2 417.22 418 379

C25H35N5O2 437.28 438 380

C25H27FN4O2 434.21 435 381

C26H27F3N4O2 484.21 485 382

C26H27F3N4O 468.21 469 383

C24H31ClN4O2 442.21 443 384

C25H28N4O 400.23 401 385

C26H30N4O2 430.24 431 386

C23H32N4O2 396.25 397 387

C25H34N4O2 422.27 423 388

C24H31ClN4O 426.22 427 389

C25H34N4O 406.27 407 390

C25H31F3N4O 460.24 461 391

C25H31F3N4O2 476.24 477 392

C23H31N5O4 441.24 442 393

C24H30N4O3 422.23 423 394

C24H32ClN5O 441.23 442 395

C25H27ClN4O 434.19 435 396

C25H28N4O 400.23 401 397

C24H28N6O 416.23 417 398

C25H34N4O2 422.27 423 399

C28H34N4O 442.27 443 400

C25H27N5O3 445.21 446 401

C25H27ClN4O 434.19 435 402

C24H31ClN4O2 442.21 443 403

C24H33N5O 407.27 408 404

C22H30N4O2 382.24 383 405

C25H34N4O 406.27 407 406

C22H22Cl2F6N4O2 558.10 559 407

C26H27F3N4O2 484.21 485 408

C24H31FN4O 410.25 411 409

C24H31FN4O 410.25 411 410

C24H31FN4O 410.25 411 411

C25H34N4O 406.27 407 412

C25H34N4O 406.27 407 413

C24H32N4O2 408.25 409 414

C22H26N6O 390.22 391 415

C26H27BrN4O 490.14 491 416

C21H24N6OS 408.17 409 417

C26H27N5O 425.22 426 418

C24H32N4O 392.26 393 419

C25H27ClN4O2 450.18 451 420

C24H30N4O3 422.23 423 421

C24H29ClN4O2 440.20 441 422

C26H31ClN4O2 466.21 467 423

C28H35ClN4O 478.25 479 424

C28H38N4O4 494.29 495 425

C24H31ClN4O2 442.21 443 426

C25H33ClN4O2 456.23 457 427

C25H28N4O3 432.22 433 428

C25H29FN4O2 436.23 437 429

C24H30BrN5O2 499.16 500 430

C25H29ClN4O2 452.20 453 431

C25H32N4O3 436.25 437 432

C24H32BrN5O2 501.17 502 433

C22H30N6O 394.25 395 434

C24H30F3N5O 461.24 462 435

C21H29N7O 395.24 396 436

C23H31N5O 393.25 394 437

C22H30N6O 394.25 395 438

C21H29N7O 395.24 396 439

C23H30ClN5O 427.21 428 440

C23H30ClN5O 427.21 428 441

C23H30ClN5O 427.21 428 442

C23H30FN5O 411.24 412 443

C23H30FN5O 411.24 412 444

C24H33N5O 407.27 408 445

C24H33N5O 407.27 408 446

C24H33N5O 407.27 408 447

C24H33N5O 407.27 408 448

C24H30F3N5O 461.24 462 449

C24H30F3N5O 461.24 462 450

C24H30N6O 418.25 419 451

C24H33N5O2 423.26 424 452

C24H33N5O2 423.26 424 453

C24H33N5O2 423.26 424 454

C25H33N5O2 435.26 436 455

C24H29ClF3N5O 495.20 496 456

C24H32ClN5O 441.23 442 457

C25H35N5O 421.28 422 458

C23H29Cl2N5O 461.17 462 459

C23H29F3N6O 462.24 463 460

C23H29F3N6O 462.24 463 461

C23H28ClF3N6O 496.20 497 462

C25H35N5O2 437.28 438 463

C23H29Cl2N5O 461.17 462 464

C25H35N5O 421.28 422 465

C23H29Cl2N5O 461.17 462 466

C25H35N5O3 453.27 454 467

C24H32ClN5O2 457.22 458 468

C23H38N6O 414.31 415 469

C23H29F2N5O 429.23 430 470

C24H30N6O 418.25 419 471

C25H35N5O 421.28 422 472

C23H37N5O 399.30 400 473

C23H32N6O 408.26 409 474

C23H32N6O 408.26 409 475

C26H37N5O 435.30 436 476

C28H36ClN5O2 509.26 510 477

C25H34N4O 406.27 407 478

C25H31FN4O2 438.24 439 479

C23H27ClFN5O 443.96 444 480

C23H30FN5O2 427.53 428 481

C23H29F2N5O2 445.52 446 482

C23H27F2N5O 427.50 428 483

C23H29ClFN5O2 461.97 462 484

C28H37FN4O4 512.28 513 485

C28H32FN5O4 521.24 522 486

C23H30ClN5O2 443.98 444 487

C23H29ClFN5O2 461.97 462 488

C26H34N4O2 434.27 435 489

C30H36N4O 468.29 469 490

C26H34N4O3 450.26 451 491

C25H32N4O2 420.25 421 492

C26H34N4O3 450.26 451 493

C25H30N4O3 434.23 435 494

C26H35N5O2 449.28 450 495

C25H30FN5O2 451.24 452 496

C25H31N5OS 449.23 450 497

C26H33N5O 431.27 432 498

C27H35N5O 445.28 446 499

C25H31F3N4O2 476.24 477 500

C26H35N5O3S 497.25 498 501

C25H31N5O3 449.24 450 502

C23H29ClN4O 412.20 413 503

C23H29FN4O 396.23 397 504

C25H31N5O 417.25 418 505

C24H30N6O3 450.24 451 506

C24H31FN4O2 426.24 427 507

C25H31FN4O 422.25 423

TABLE 7 Ex. Molecular Monoisotopic M + No. Structure formula molecular wt. H⁺ 508

C26H33N3O2 419.26 420 509

C26H34N4O2 434.27 435 510

C26H27N3O2 413.21 414 511

C30H35N3O2 469.27 470 512

C27H29N3O2 427.23 428 513

C27H28N4O6S 536.17 537 514

C25H33N3O3 423.25 424 515

C24H29N3O3 407.22 408 516

C25H33N3O3 423.25 424 517

C27H29N3O3 443.22 444 518

C27H29N3O2 427.23 428 519

C27H29N3O2 427.23 428 520

C27H29N3O2 427.23 428 521

C27H26F3N3O2 481.20 482 522

C27H26F3N3O2 481.20 482 523

C28H31N3O4 473.23 474 524

C27H28N4O4S 504.18 505 525

C26H25ClFN3O3 481.16 482 526

C24H25N3O3 403.19 404 527

C24H25N3O2S 419.17 420 528

C25H28N4O2 416.22 417 529

C24H24ClN3O3 437.15 438 530

C24H24FN3O3 421.18 422 531

C25H33N3O 391.26 392 532

C25H27N3O2 401.21 402 533

C25H27N3O 385.21 386 534

C23H31N3O2 381.24 382 535

C26H29N3O2 415.23 416 536

C25H27N3O 385.21 386 537

C24H31N3O 377.25 378 538

C25H26N4O4 446.20 447 539

C26H29N3O 399.23 400 540

C26H29N3O2 415.23 416 541

C28H33N3O2 443.26 444 542

C25H29N5O4 463.22 464 543

C23H31N3O2 381.24 382 544

C25H27N3O2 401.21 402 545

C25H31N3O2 405.24 406 546

C27H31N3O 413.25 414 547

C28H33N3O 427.26 428 548

C21H22FN5O2 395.18 396 549

C25H25N3O2 399.20 400 550

C29H35N3O 441.28 442 551

C23H23ClN4O4 454.14 455 552

C25H26FN3O2 419.20 420 553

C26H29N3O 399.23 400 554

C27H29N3O2 427.23 428 555

C28H38N4O3 478.29 479 556

C25H26FN3O 403.21 404 557

C23H24FN3OS 409.16 410 558

C26H26F3N3O2 469.20 470 559

C29H34N4O2 470.27 471 560

C25H26N4O4 446.20 447 561

C24H33N3O2 395.26 396 562

C24H33N3O2 395.26 396 563

C25H26FN3O 403.21 404 564

C26H29N3O2 415.23 416 565

C25H26ClN30 419.18 420 566

C26H29N3O2 415.23 416 567

C26H29N3O2 415.23 416 568

C25H26FN3O 403.21 404 569

C26H27N3O3 429.20 430 570

C26H29N3O 399.23 400 571

C26H29N3O 399.23 400 572

C26H26F3N3O 453.20 454 573

C26H26F3N3O 453.20 454 574

C26H35N3O2 421.27 422 575

C27H31N3O2 429.24 430 576

C25H26ClN3O 419.18 420 577

C25H25Cl2N3O 453.14 454 578

C24H28N4O2 404.22 405 579

C27H31N3O3S 477.21 478 580

C25H31N5O3 449.24 450 581

C24H31N3O2 393.24 394 582

C23H31N3O2 381.24 382 583

C25H25F3N4O2 470.19 471 584

C24H39N3O 385.31 386 585

C25H25Cl2N3O 453.14 454 586

C25H26BrN3O 463.13 464 587

C25H32ClN3O 425.22 426 588

C25H32N4O2 420.25 421 589

C24H26N4O4 434.20 435 590

C24H30FN3O2 411.23 412 591

C26H28FN3O 417.22 418 592

C25H25N5O2 427.20 428 593

C26H26N4O 410.21 411 594

C26H32FN3O2 437.25 438 595

C25H26ClN3O 419.18 420 596

C24H26N4O 386.21 387 597

C26H26F3N3O 453.20 454 598

C27H31N3O3 445.24 446 599

C28H29N3O3 455.22 456 600

C24H33N3O2 395.26 396 601

C25H27N3O 385.21 386 602

C28H30N4O2 454.24 455 603

C26H36N4O4 468.27 469 604

C28H38N4O3 478.29 479 605

C22H28FN3O2S 417.55 418 606

C23H29N3O3 395.22 396 607

C27H33N3O3 447.25 448 608

C27H37N3O4 467.28 468 609

C29H39N3O3 477.30 478 610

C27H29FN4O3 476.22 477 611

C25H34N4O4 454.26 455 612

C27H35N3O2 433.27 434 613

C25H31N3O3 421.24 422 614

C28H32N4O4 488.24 489 615

C27H35ClN4O3 498.24 499 616

C26H29N5O4 475.22 476 617

C28H36F3N3O4 535.27 536 618

C27H38N4O4 482.29 483 619

C27H38N4O4 482.29 483 620

C28H39N3O5 497.29 498 621

C23H23N5O3 417.18 418 622

C25H26N4O2 414.21 415 623

C28H35ClN4O4 526.23 527 624

C28H39N3O4 481.29 482 625

C27H36ClN3O4 501.24 502 626

C27H35F2N3O4 503.26 504 627

C27H36FN3O4 485.27 486 628

C27H36FN3O4 485.27 486 629

C28H39N3O4 481.29 482 630

C28H36F3N3O4 535.27 536 631

C27H35ClFN3O4 519.23 520 632

C28H36N4O4 492.27 493 633

C28H38ClN3O4 515.26 516 634

C31H39N3O4 517.29 518 635

C27H36BrN3O4 545.19 546 636

C28H36N4O4 492.27 493 637

C26H35ClN4O4 502.23 503 638

C27H35F2N3O4 503.26 504 639

C27H36BrN3O4 545.19 546 640

C27H35F2N3O4 503.26 504 641

C23H31N3O3 397.24 398 642

C24H33N3O3 411.25 412 643

C27H37N3O5 483.27 484 644

C25H34N4O4 454.26 455 645

C27H36FN3O4 485.27 486 646

C27H24FN3O3 457.18 458 647

C27H33N3O2 431.26 432 648

C23H31N3O3 397.24 398 649

C25H24FN3O2 417.18 418 650

C27H36N4O3 464.28 465 651

C25H26N4O2 414.21 415 652

C31H33FN4O3 528.25 529 653

C32H38N4O2 510.30 511 654

C28H38N4O2 462.30 463 655

C29H34N4O2 470.27 471 656

C26H26ClN3O2 447.17 448 657

C29H38N4O2 474.30 475 658

C27H29N3O3 443.22 444 659

C24H29N5O4 451.22 452 660

C25H33N3O2 407.26 408 661

C25H30N4O3S2 498.18 499 662

C28H29FN4O3 488.22 489 663

C31H44N4O2 504.35 505 664

C32H40N4O2 512.32 513 665

C25H30N6O3 462.24 463 666

C25H30N6O3 462.24 463 667

C30H33N5O4 527.25 528 668

C27H27N3O4 457.20 458 669

C26H31N5O3 461.24 462 670

C21H27N3O4 385.20 386 671

C25H30N6O3 462.24 463 672

C31H35FN4O3 530.27 531 673

C26H32N6O3 476.25 477 674

C27H42FN3O4 491.32 492 675

C25H32N4O 404.26 405 676

C27H30N4O2 442.24 443 677

C29H34N4O2 470.27 471 678

C26H28FN3O 417.22 418 679

C25H32FN3O2 425.55 426 680

C23H30N4O2 394.24 395 681

C25H32N4O2 420.25 421 682

C24H30N4O2 406.24 407 683

C26H28N4O2 428.22 429 684

C23H28N4O2 392.22 393 685

C26H34N4O2 434.27 435 686

C24H27N5O3 433.21 434 687

C24H32N4O2 408.25 409 688

C22H30N4O2 382.24 383 689

C24H33N5O 407.27 408 690

C25H28N4O2 416.22 417 691

C24H26N4O 386.21 387 692

C22H24N4OS 392.17 393 693

C21H24N4OS 380.17 381 694

C19H21N3OS2 371.11 372 695

C23H24ClN3O2 409.16 410 696

C22H24ClN3OS 413.13 414 697

C21H21ClFN3OS 417.11 418 698

C21H21Cl2N3OS 433.08 434 699

C21H21ClN4O3S 444.10 445 700

C22H23Cl2N3O2S 463.09 464 701

C22H24ClN3O2S 429.13 430 702

C23H26ClN3OS 427.15 428 703

C24H26ClN3O2S 455.14 456 704

C22H24F3N5OS 463.17 464 705

C24H23ClF3N3O2 477.14 478 706

C24H24F3N3O2 443.18 444 707

C23H28BrN5O2 485.14 486 708

C24H25F3N4O2S 490.17 491 709

C22H22N4OS 390.15 391 710

C23H25N3O2 375.20 376 711

C24H27N3O2S 421.18 422 712

C24H26ClN3O3 439.17 440 713

C21H22ClN3OS 399.12 400 714

C25H23F6N3O2 511.17 512 715

C23H30FN3O2 399.51 400 716

C26H34FN3O4 471.25 472 717

C26H29N3O2 415.23 416 718

C27H31N3O2 429.24 430 719

C26H33N3O2 419.26 420 720

C25H28N4O4 448.21 449 721

C24H33N3O2 395.26 396 722

C26H28FN3O2 433.22 434 723

C26H27N3O2 413.21 414 724

C25H33N3O2 407.26 408 725

C26H28BrN3O 477.14 478 726

C24H26FN3OS 423.18 424 727

C26H28FN3O 417.22 418 728

C27H31N3O2 429.24 430 729

C26H28ClN3O 433.19 434 730

C26H28ClN3O 433.19 434 731

C26H28ClN3O 433.19 434 732

C24H25ClN4O4 468.16 469 733

C26H28FN3O 417.22 418 734

C27H29N3O3 443.22 444 735

C27H31N3O 413.25 414 736

C27H31N3O 413.25 414 737

C26H26FN3O2 431.20 432 738

C27H29N3O2 427.23 428 739

C25H35N3O2 409.27 410 740

C26H34ClN3O 439.24 440 741

C32H36N6O3 552.28 553 742

C26H36FN3O2 411.59 412 743

C25H32N4O2 420.25 421 744

C24H30N4O2 406.24 407 745

C26H28N4O2 428.22 429 746

C27H30N4O2 442.24 443 747

C24H32N4O2 408.25 409 748

C24H30N4O2 406.24 407 749

C24H32N4O2 408.25 409 750

C25H32N4O2 420.25 421 751

C24H30N4O2 406.24 407 752

C25H34N4O2 422.27 423 753

C22H30N4O2 382.24 383 754

C27H35FN4O6 530.25 531 755

C24H32N4O2 408.25 409 756

C26H27FN4O2 446.21 447 757

C25H34N4O2 422.27 423 758

C24H32N4O2 408.25 409 759

C24H26N4O3 418.20 419 760

C24H30N4O2 406.24 407 761

C26H32N4O2 432.25 433 762

C26H34N4O2 434.27 435 763

C26H34N4O3 450.26 451 764

C25H31ClN4O2 454.21 455 765

C24H30N4O2 406.24 407 766

C25H34N4O2 422.27 423 767

C24H26N4O2S 434.18 435 768

C26H34N4O2 434.27 435 769

C23H30ClN3O2 415.20 416 770

C24H32FN3O2 413.25 414 771

C23H28FN3O2 397.22 398 772

C24H30FN3O2 411.23 412 773

C24H30FN3O2 411.23 412 774

C25H33FN4O2 440.26 441 775

C26H33FN4O3 468.25 469 776

C23H26N4O 374.21 375 777

C28H30N4O 438.24 439 778

C21H25N5O2 379.20 380 779

C26H27N3O2 413.21 414 780

C26H26N4O 410.21 411 781

C25H31N5O 417.25 418 782

C21H24N6OS 408.17 409 783

C22H25N5O 375.21 376 784

C24H28F3N5O 459.23 460 785

C25H30N6O 430.25 431 786

C26H32N6O 444.26 445 787

C25H27N3OS 417.19 418 788

C30H34N4O 466.27 467 789

C24H30N4OS 422.21 423 790

C24H26ClN3O3S2 503.11 504 791

C23H23Cl2N3O3 459.11 460 792

C24H26ClN3O2 423.17 424 793

C23H26N4OS 406.18 407 794

C25H27N3O3S 449.18 450 795

C23H25ClN4OS 440.14 441 796

C23H25N3O3 391.19 392 797

C23H23F3N4O2 444.18 445 798

C23H28N4O3 408.22 409 799

C25H30N4O 402.24 403 800

C26H29N3O2 415.23 416 801

C27H29N5O 439.24 440 802

C22H24F3N3O2 419.18 420 803

C22H25N3O3 379.19 380 804

C22H24N4O 360.20 361 805

C22H23F4N3O 421.18 422 806

C23H29N3O2 379.23 380 807

C26H29N3O2 415.23 416 808

C27H30FN3O 431.24 432 809

C22H23F3N4O2 432.18 433 810

C25H25N3O2 399.20 400 811

C25H28N40 400.23 401 812

C21H24F3N3O3 423.18 424 813

C22H30N4O 366.24 367 814

C24H31FN4O2 426.24 427 815

C25H31FN4O3 454.24 455 816

C25H30FN3O2 423.23 424 817

C23H30N4O 378.24 379 818

C24H27N3O4 421.20 422 819

C30H34FN3O4 519.25 520 820

C30H34FN3O4 519.25 520 821

C29H34FN3O4S 539.22 540 822

C29H38FN3O3 495.29 496 823

C30H40FN3O3 509.30 510 824

C31H35F2N3O3 535.27 536 825

C28H38FN3O4 499.29 500 826

C30H39ClFN3O3 543.27 544 827

C29H33ClFN3O5 557.21 558 828

C29H38FN3O4 511.29 512 829

C29H33FN4O6 552.24 553 830

C28H38FN3O4 499.29 500 831

C30H34FN3O3 503.26 504 832

C31H36FN3O4 533.27 534 833

C33H37FN4O4 572.28 573 834

C31H36FN3O3 517.27 518 835

C29H40FN3O4 513.30 514 836

C30H33F2N3O3 521.25 522 837

C25H32N4O2 420.25 421 838

C23H30N4O2S 426.21 427 839

C23H30N4O3 410.23 411 840

C25H36N4O2 424.28 425 841

C24H36N4O2 412.28 413 842

C23H34N4O2 398.27 399 843

C23H34N4O2 398.27 399 844

C25H31FN4O2 438.24 439 845

C26H34N4O2 434.27 435 846

C25H31ClN4O2 454.21 455 847

C23H36N4O2 400.28 401 848

C23H36N4O2 400.28 401 849

C26H25N3O4S 475.16 476 850

C21H23N3O 333.18 334 851

C22H25N5O 375.21 376 852

C21H23N5OS 393.16 394 853

C20H22N6OS 394.16 395 854

C20H25N5OS 383.18 384 855

C23H29N5O4 439.22 440 856

C25H32N4O3S 468.22 469 857

C22H30N4OS2 430.19 431 858

C24H31BrN4OS 502.14 503 859

C24H24FN3O3 421.18 422 860

C28H27ClN4O 470.19 471 861

C23H31N5OS 425.23 426 862

C22H30N4O5S 462.19 463 863

C23H32N4O4S 460.21 461 864

C27H29N5O 439.24 440 865

C22H25N5O2 391.20 392 866

C26H29N3O4S 479.19 480 867

C23H23F3N4OS 460.15 461 868

C22H29N7O2 423.24 424 869

C25H26N6O 426.22 427 870

C26H32N4O2 432.25 433 871

C24H27N3O2 389.21 390 872

C27H29N5O 439.24 440 873

C23H28N4O3S 440.19 441 874

C28H34N4OS 474.24 475 875

C24H28N4O3S 452.19 453 876

C23H23ClN4O3 438.15 439 877

C23H26FN5O 407.21 408 878

C25H27ClN4O2 450.18 451 879

C24H27N5O 401.22 402 880

C24H30F3N5O 461.24 462 881

C22H23ClN4O2 410.15 411 882

C23H26N4OS 406.18 407 883

C24H26N4O 386.21 387 884

C24H26N4O 386.21 387 885

C24H26N4O 386.21 387 886

C21H23F3N6OS 464.16 465 887

C23H30N4O3S 442.20 443 888

C24H26N4O2 402.21 403 889

C24H25F3N4OS 474.17 475 890

C27H29N3O 411.23 412 891

C26H29N3O 399.23 400 892

C28H31N3O2 441.24 442 893

C23H28N4O2 392.22 393 894

C27H29N3O2 427.23 428 895

C21H25N7O 391.21 392 896

C21H28N4OS 384.20 385 897

C23H26ClN5O 423.18 424 898

C21H23N5OS 393.16 394 899

C26H26ClN5O 459.18 460 900

C23H27N5O 389.22 390 901

C25H34N4O 406.27 407 902

C24H30N4O2 406.24 407 903

C23H30ClN3O2 415.20 416 904

C25H25F2N3O2 437.19 438 905

C29H39FN4O2 494.31 495 906

C29H32F2N4O2 506.25 507 907

C30H35FN4O2 502.27 503 908

C27H37FN4O3 484.29 485 909

C27H37FN4O3 484.29 485 910

C25H34FN3O3 443.26 444 911

C24H30Cl2FN3O2 481.17 482 912

C24H31FN4O4 458.23 459 913

C24H31ClFN3O2 447.21 448 914

C26H36FN3O2 441.28 442 915

C25H32Cl2FN3O3 511.18 512 916

C24H28F5N3O2 485.21 486 917

C24H31F2N3O2 431.24 432 918

C26H34FN3O3 455.26 456 919

C28H40FN3O3 485.30 486 920

C25H34FN5O 439.27 440 921

C23H31FN4O2 414.24 415 922

C24H26FN3O3 423.20 424 923

C26H28FN3O2 433.22 434 924

C26H33FN4O2 452.26 453 925

C26H32ClFN4O2 486.22 487 926

C25H31FN4O2 438.24 439 927

C26H31F3N4O3 504.23 505 928

C26H33ClN4O3 484.22 485 929

C25H31ClN4O2 454.21 455 930

C24H31ClFN3O2 447.21 448 931

C25H34FN3O2 427.26 428 932

C27H33FN4O2 464.26 465 933

C26H28FN3O2 433.22 434 934

C25H28FN3O2S 453.19 454 935

C25H32FN3O 409.25 410 936

C26H34FN3O 423.27 424 937

C27H29F2N3O 449.23 450 938

C24H32FN3O2 413.25 414 939

C26H33ClFN3O 457.23 458 940

C24H32FN3O2 413.25 414 941

C26H28FN3O 417.22 418 942

C27H30FN3O2 447.23 448 943

C29H31FN4O2 486.24 487 944

C27H30FN3O 431.24 432 945

C25H34FN3O2 427.26 428 946

C26H27F2N3O 435.21 436 947

C25H27FN4O2 434.52 435 948

C25H27FN4O4 466.20 467 949

C24H29FN4O3 440.22 441 950

C27H30FN3O2 447.23 448 951

C23H31FN4O 398.25 399 952

C24H26ClFN4OS 472.15 473 953

C25H25F2N3O3 453.19 454 954

C24H27F2N5O 439.22 440 955

C26H31F2N3O2 455.24 456 956

C23H31N3O2 381.24 382 957

C24H33N3O2 395.26 396 958

C24H33N3O2 395.26 396 959

C26H29N3O2 415.23 416 960

C25H29N5O2 431.23 432 961

C24H24ClFN4O3 470.15 471 962

C27H36FN3O2 453.61 454 963

C24H30N4O2 406.24 407 964

C24H28N4O2 404.22 405 965

C27H29N5O 439.24 440 966

C25H28N4O4S 480.18 481 967

C24H26N4O2 402.21 403 968

C27H27BrN4O2 518.13 519 969

C22H24ClN5O 409.17 410 970

C22H23F2N3O3 415.17 416 971

C21H23N5OS 393.16 394 972

C23H24ClN3OS 425.13 426 973

C22H24N4O3 392.18 393 974

C25H27ClN4O2 450.18 451 975

C25H30N4O 402.24 403 976

C22H25N5O 375.21 376 977

C22H27N3O3S 413.18 414 978

C20H23F3N4OS 424.15 425 979

C21H24F3N3OS 423.16 424 980

C26H24BrF3N6O 572.11 573 981

C23H25ClN4OS 440.14 441 982

C24H32N4O3S 456.22 457 983

C24H31ClN4O3S 490.18 491 984

C23H25N3O4S 439.16 440 985

C26H32N4O3 448.25 449 986

C26H32N4O 416.26 417 987

C22H27N3OS 381.19 382 988

C24H31N3O2 393.24 394 989

C22H24F3N3OS 435.16 436 990

C24H33N3O 379.26 380 991

C22H29N3O2 367.23 368 992

C25H35N3O 393.28 394 993

C25H30N4O 402.24 403 994

C22H26N4OS2 426.15 427 995

C29H32N4O2 468.25 469 996

C23H26FN5O 407.21 408 997

C28H28ClN5O 485.20 486 998

C20H23N5O2S 397.16 398 999

C25H26N6O 426.22 427 1000

C22H24N4O2 376.19 377 1001

C26H35FN4O2 454.27 455 1002

C25H34FN3O2 427.57 428 1003

C24H25FN4O 404.20 405 1004

C25H30N4O2 418.24 419 1005

C26H31FN4O2 450.24 451 1006

C25H34N4O2 422.27 423 1007

C24H30N4O2 406.24 407 1008

C27H30N4O2 442.24 443 1009

C27H29FN4O2 460.23 461 1010

C26H34N4O2 434.27 435 1011

C26H26ClFN4O2 480.17 481 1012

C26H27FN4O2 446.21 447 1013

C25H27N5O2 429.22 430 1014

C27H36N4O2 448.28 449 1015

C25H29N5O3 447.23 448 1016

C29H32N4O2 468.25 469 1017

C26H27FN4O2 446.21 447 1018

C23H30N4O3 410.23 411 1019

C23H30N4O3 410.23 411 1020

C24H30N4O2 406.24 407 1021

C24H28N6O2 432.23 433 1022

C25H27N5O2 429.22 430 1023

C25H34N4O2 422.27 423 1024

C25H28N4O2S 448.19 449 1025

C25H29N5O2 431.23 432 1026

C26H26F2N4O2 464.20 465 1027

C24H27N5O2 417.22 418 1028

C29H38N4O2 474.30 475 1029

C27H36N4O3 464.28 465 1030

C24H27N5O2 417.22 418 1031

C27H36N4O2 448.28 449 1032

C27H36N4O2 448.28 449 1033

C27H38N4O2 450.30 451 1034

C29H32N4O2 468.25 469 1035

C27H34N4O2 446.27 447 1036

C26H27ClN4O2 462.18 463 1037

C22H24N6O2S 436.17 437 1038

C23H25N5O3 419.20 420 1039

C25H32N4O2 420.25 421 1040

C26H27ClN4O2 462.18 463 1041

C27H30N4O2 442.24 443 1042

C24H30N4O3 422.23 423 1043

C27H30N4O2 442.24 443 1044

C30H38N4O2 486.30 487 1045

C29H34N4O3 486.26 487 1046

C27H28F2N4O3 494.21 495 1047

C25H32N4O3 436.25 437 1048

C27H36N4O2 448.28 449 1049

C23H27F3N4O2 448.21 449 1050

C26H32N4O2 432.25 433 1051

C26H36N4O2 436.28 437 1052

C22H28FN3O2 385.22 386 1053

C27H30N4O2 442.24 443 1054

C21H24N6O 376.20 377 1055

C25H27N5OS 445.19 446 1056

C24H26N4O 386.21 387 1057

C22H24N4O2 376.19 377 1058

C27H30N4O 426.24 427 1059

C24H32N4O 392.26 393 1060

C22H26N6O 390.22 391 1061

C24H27N5O2 417.22 418 1062

C23H26ClN5O 423.18 424 1063

C24H26ClN3O2 423.17 424 1064

C24H25ClN6O2 464.17 465 1065

C24H27N3OS 405.19 406 1066

C20H21ClN4O2S 416.11 417 1067

C25H26N4O3S 462.17 463 1068

C26H28N4O4 460.21 461 1069

C30H42FN3O4 527.32 528 1070

C31H42FN3O4 539.32 540 1071

C27H30N4O2 442.24 443 1072

C28H32N4O3 472.25 473 1073

C25H32FN3O2 425.25 426 1074

C27H30FN3O2 447.23 448 1075

C27H30FN3O 431.24 432 1076

C28H27FN4O3 486.21 487 1077

C28H28BrFN4O2 550.14 551 1078

C28H31FN4O2 474.24 475 1079

C26H31FN4O 434.25 435 1080

C26H29FN4O2 448.23 449 1081

C28H30FN5O 471.24 472 1082

C29H31FN4O 470.25 471 1083

C27H30FN3OS 463.21 464 1084

C25H28FN5OS 465.20 466 1085

C26H29FN4OS 464.20 465 1086

C28H29FN4O2 472.23 473 1087

C27H30FN3O2 447.23 448 1088

C27H29ClFN3O2 481.19 482 1089

C25H34FN3O 411.27 412 1090

C25H34FN3O2 427.26 428 1091

C23H30FN3O2 399.23 400 1092

C24H32FN3O2 413.25 414 1093 — C26H32FN3O2 437.25 438 1094 — C30H36N4O4 516.27 517 1095

C25H31F2N3O2 443.24 444 1096

C25H31F2N3O2 443.24 444 1097

C26H27F2N3O2 451.21 452 1098

C26H34F2N4O 456.27 457 1099

C27H27FN4O2 458.21 459 1100

C27H27FN4O2 458.21 459 1101

C24H30FN3O2 411.23 412 1102

C23H25FN4OS 424.17 425 1103

C28H29FN4O2 472.23 473 1104

C25H32FN3O2 425.25 426 1105

C24H27FN4OS 438.19 439 1106

C25H34FN3O3 443.26 444 1107

C26H27F2N3O2 451.21 452 1108

C27H36FN3O2 453.28 454 1109

C26H26F3N3O2 469.20 470 1110

C25H27FN4O2 434.21 435 1111

C25H34FN3O2 427.26 428 1112

C26H34FN3O2 439.26 440 1113

C27H36FN3O2 453.28 454 1114

C25H34FN3O2 427.26 428 1115

C25H33ClFN3O3 477.22 478 1116

C24H31F2N3O2 431.24 432 1117

C25H32FN3O2 425.25 426 1118

C27H30FN3O3S 495.62 496 1119

C23H27F4N3O 437.21 438 1120

C26H36FN3O2 441.28 442 1121

C25H27FN4O2 434.21 435 1122

C25H33N3O2 407.26 408 1123

C24H31N3O2 393.24 394 1124

C25H34FN3O2 427.26 428 1125

C23H30FN3O2 399.23 400 1126

C27H29ClFN3O2 481.19 482 1127

C22H25F4N3OS 455.17 456 1128

C25H32FN3O2 425.25 426 1129

C25H32F2N4O 442.25 443 1130

C26H29FN4O2 448.23 449

TABLE 8 Ex. Molecular Monoisotopic M + No. Structure formula molecular wt. H⁺ 1131

C23H23Cl2N3O2 443.12 444 1132

C23H23ClFN3O2 427.15 428 1133

C24H26FN3O2 407.20 408 1134

C28H33N3O4 475.25 476 1135

C29H34N4O5 518.25 519 1136

C33H41N3O4 543.31 544 1137

C29H36N4O4 504.27 505 1138

C29H32N4O4 500.24 501 1139

C28H30F3N3O4 529.22 530 1140

C22H22Cl2N4OS 460.09 461 1141

C22H23ClN4OS 426.13 427 1142

C22H23FN4OS 410.16 411 1143

C23H25FN4OS 424.17 425 1144

C23H22ClF3N4OS 494.12 495 1145

C26H26N4OS 442.18 443 1146

C25H25Cl2N3O 453.14 454 1147

C23H25N3OS 391.17 392 1148

C23H23F3N4OS 460.15 461 1149

C22H23N5O3S 437.15 438 1150

C22H24N4OS 392.17 393 1151

C22H22Cl2N4OS 460.09 461 1152

C22H22ClFN4OS 444.12 445 1153

C20H22N4OS2 398.12 399 1154

C23H26N4O2S 422.18 423 1155

C23H23F3N4OS 460.15 461 1156

C23H26N4OS 406.18 407 1157

C23H26N4O2S 422.18 423 1158

C24H27N5O2S 449.19 450 1159

C22H23ClN4OS 426.13 427 1160

C22H23FN4OS 410.16 411 1161

C26H26N4OS 442.18 443 1162

C23H26N4OS2 438.15 439 1163

C22H22Cl2N4OS 460.09 461 1164

C24H28N4O2S 436.19 437 1165

C24H28N4O2S 436.19 437 1166

C26H32N4OS 448.23 449 1167

C23H23N5OS 417.16 418 1168

C28H28N4OS 468.20 469 1169

C24H28N4O2S 436.19 437 1170

C23H24N4O3S 436.16 437 1171

C26H32N4O2S 464.23 465 1172

C23H26N4OS2 438.15 439 1173

C24H28N4OS2 452.17 453 1174

C24H28N4OS 420.20 421 1175

C23H23F3N4O2S 476.15 477 1176

C24H28N4O3S 452.19 453 1177

C25H30N4OS 434.21 435 1178

C25H30N4OS 434.21 435 1179

C23H26N4O2S 422.18 423 1180

C22H25N5O2S 423.17 424 1181

C24H24N4OS2 448.14 449 1182

C23H23F3N4O2S 476.15 477 1183

C24H22F6N4OS 528.14 529 1184

C23H25FN4OS 424.17 425 1185

C24H28N4OS 420.20 421 1186

C24H28N4OS 420.20 421 1187

C25H26N4O3 430.20 431 1188

C27H31N3O2 429.24 430 1189

C25H25ClFN3O 437.17 438 1190

C25H25Cl2N3O 453.14 454 1191

C26H26N4O 410.21 411 1192

C27H29N3O2 427.23 428 1193

C27H29N3O2 427.23 428 1194

C25H25F2N3O 421.20 422 1195

C25H25F2N3O 421.20 422 1196

C26H28N4O3 444.22 445 1197

C27H32N4O 428.26 429 1198

C25H28N4O2 416.22 417 1199

C27H29N3O3 443.22 444 1200

C24H28N4O2 404.22 405 1201

C23H25N3O2 375.20 376 1202

C24H25FN4O 404.20 405 1203

C22H25N5O 375.21 376 1204

C26H28FN3O 417.22 418 1205

C26H28FN3O 417.22 418 1206

C24H25ClN4O 420.17 421 1207

C24H25FN4O 404.20 405 1208

C24H25FN4O 404.20 405 1209

C26H28FN3O2 433.22 434 1210

C27H30N4O2 442.24 443 1211

C25H26N4O3 430.20 431 1212

C26H25FN4O 428.20 429 1213

C24H25FN4O 404.20 405 1214

C24H25FN4O 404.20 405 1215

C26H28FN3O3S 481.18 482 1216

C27H29FN4O2 460.23 461 1217

C28H31FN4O2 474.24 475 1218

C26H25F4N3O2 487.19 488 1219

C26H28FN3O3S 481.18 482 1220

C26H25F4N3O2 487.19 488 1221

C26H25FN4O 428.20 429 1222

C27H29FN4O2 460.23 461 1223

C26H25F4N3O2 487.19 488 1224

C25H25F2N3O 421.20 422 1225

C25H32N4O3S 468.22 469 1226

C24H31N5O 405.25 406 1227

C24H31N5O2 421.25 422 1228

C23H28FN5O 409.23 410 1229

C26H31N5O 429.25 430 1230

C25H29N5OS 447.21 448 1231

C26H34N4O 418.27 419 1232

C26H32N4O2 432.25 433

TABLE 9 Ex. Molecular Monoisotopic M + No. Structure formula molecular wt. H⁺ 1233

C31H29N3O2 475.23 476 1234

C30H35N3O2 469.27 470 1235

C28H30N4O3S 502.20 503 1236

C29H30FN3O3S 519.20 520 1237

C28H30N4O3S 502.20 503

TABLE 10 Ex. Molecular Monoisotopic M + No. Structure formula molecular wt. H⁺ 1238

C26H35N3O2 421.27 422 1239

C26H35N3O2 421.27 422 1240

C25H31F2N3O2 443.24 444 1241

C27H35N3O2 433.27 434 1242

C26H35N3O2 421.27 422 1243

C25H36N4O2 424.28 425 1244

C24H33N3O3 411.25 412 1245

C26H37N3O3 439.28 440 1246

C27H37N3O2 435.29 436 1247

C27H37N3O2 435.29 436 1248

C27H33N5O2 459.26 460 1249

C26H35N3O3 437.27 438 1250

C29H34FN3O2 475.26 476 1251

C27H32N4O2 444.25 445 1252

C24H33N3O2 395.26 396 1253

C23H31N3O2 381.24 382 1254

C25H33N3O3 423.25 424 1255

C23H28F3N3O2 435.21 436 1256

C23H30FN3O2 399.23 400 1257

C27H37N3O3 451.28 452 1258

C24H33N3O3 411.25 412 1259

C25H33N3O2 407.26 408 1260

C25H33N3O2 407.26 408 1261

C25H35N3O2 409.27 410 1262

C25H35N3O2 409.27 410 1263

C25H35N3O2 409.27 410 1264

C25H35N3O2 409.27 410 1265

C27H35N5O2 461.28 462 1266

C28H38N4O3 478.29 479 1267

C26H36N4O2 436.28 437 1268

C26H38N4O2 438.30 439 1269

C30H35N3O2 469.27 470 1270

C27H32N4O2 444.25 445 1271

C27H36N4O3 464.28 465 1272

C27H37N3O2 435.29 436 1273

C30H35N3O2 469.27 470 1274

C26H35N3O2 421.27 422 1275

C29H39N3O2 461.30 462 1276

C29H43N3O2 465.34 466 1277

C28H39N3O2 449.30 450 1278

C28H37N3O2 447.29 448 1279

C28H40N4O2 464.32 465 1280

C30H35N3O2 469.27 470 1281

C30H34N4O2 482.27 483 1282

C30H35N3O3 485.27 486 1283

C25H33N3O4S 471.22 472 1284

C29H39N3O2 461.30 462 1285

C26H33N3O3 435.25 436 1286

C27H35N5O2 461.28 462 1287

C25H35N3O2 409.27 410 1288

C26H35N3O4S 485.23 486 1289

C27H38N4O2 450.30 451 1290

C26H31N3O2S 449.21 450 1291

C29H41N3O2 463.32 464 1292

C25H32N4O3 436.25 437 1293

C26H35N3O3 437.27 438 1294

C25H30N4O2S 450.21 451 1295

C24H31N3O2 393.24 394 1296

C25H35N5O2 437.28 438 1297

C27H37N5O2 463.30 464 1298

C26H32N6O2S 492.23 493 1299

C24H33N5O3 439.26 440 1300

C28H40FN3O3 485.30 486 1301

C27H36FN3O2 453.28 454 1302

C31H37N5O2 511.30 512 1303

C28H39N5O2 477.31 478 1304

C27H39N5O2 465.31 466 1305

C27H39N5O2 465.31 466 1306

C26H35N5O2S 481.25 482 1307

C26H33N7O2 475.27 476 1308

C26H35N5O2 449.28 450 1309

C26H37N5O3 467.29 468 1310

C26H37N5O3 467.29 468 1311

C26H37N5O3 467.29 468 1312

C27H37N5O3 479.29 480 1313

C27H39N5O3 481.30 482 1314

C28H38N6O2 490.31 491 1315

C28H39N5O4 509.30 510 1316

C28H39N5O2 477.31 478 1317

C29H40N6O3 520.32 521 1318

C30H44N6O2 520.35 521 1319

C30H44N6O3 536.35 537 1320

C30H34N6O2 510.27 511 1321

C33H42N6O2 554.34 555 1322

C27H35N7O2 489.29 490 1323

C29H38F3N5O2 545.30 546 1324

C29H39N7O2 517.32 518 1325

C31H37N7O2 539.30 540 1326

C26H33N7O2 475.27 476 1327

C26H37N5O2S 483.27 484 1328

C26H35N5O2 449.28 450 1329

C27H35N7O2 489.29 490 1330

C28H41N5O3 495.32 496 1331

C25H31N7O2S 493.23 494 1332

C31H39N5O3 529.30 530 1333

C30H42N6O4 550.33 551 1334

C28H41N5O2 479.33 480 1335

C29H30F2N4O2 504.58 505 1336

C25H32FN3O2 425.25 426 1337

C25H34FN3O2 427.26 428 1338

C24H32FN3O3 429.24 430 1339

C26H34FN3O2 439.26 440 1340

C26H34FN3O2 439.26 440 1341

C25H34FN3O3 443.26 444 1342

C25H34FN3O3 443.26 444 1343

C25H34FN3O3 443.26 444 1344

C27H36FN3O2 453.28 454 1345

C27H38FN3O2 455.30 456 1346

C27H38FN3O2 455.30 456 1347

C27H38FN3O2 455.30 456 1348

C26H36FN3O3 457.27 458 1349

C26H36FN3O3 457.27 458 1350

C25H34FN3O4 459.25 460 1351

C25H34FN3O4 459.25 460 1352

C28H38FN3O2 467.30 468 1353

C27H38FN3O3 471.29 472 1354

C27H38FN3O3 471.29 472 1355

C27H34FN5O2 479.27 480 1356

C29H40FN3O2 481.31 482 1357

C29H40FN3O2 481.31 482 1358

C28H39FN4O2 482.31 483 1359

C28H38FN3O3 483.29 484 1360

C28H38FN3O3 483.29 484 1361

C28H36FN5O2 493.29 494 1362

C27H35FN6O2 494.28 495 1363

C28H37FN4O3 496.29 497 1364

C29H41FN4O2 496.32 497 1365

C28H39FN4O3 498.30 499 1366

C26H32FN3O4 469.24 470 1367

C29H40FN3O3 497.30 498 1368

C25H31FN4O2 438.24 439 1369

C26H34FN3O2 439.26 440 1370

C26H36FN3O2 441.28 442 1371

C25H34FN3O3 443.26 444 1372

C27H36FN3O2 453.28 454 1373

C26H34FN3O3 455.26 456 1374

C28H38FN3O2 467.30 468 1375

C27H37FN4O2 468.29 469 1376

C26H34FN3O2S 471.24 472 1377

C26H36FN3O4 473.27 474 1378

C28H41FN4O2 484.32 485 1379

C28H37FN4O3 496.29 497 1380

C28H37FN4O3 496.29 497 1381

C32H38FN3O2 515.29 516 1382

C31H38FN3O3 519.29 520 1383

C31H43FN4O2 522.34 523 1384

C27H36FN3O3 469.27 470 1385

C27H36FN3O3 469.27 470 1386

C28H34F3N3O3 517.26 518 1387

C27H36FN3O4S 517.24 518 1388

C30H41FN4O3 524.32 525 1389

C27H36FN3O3 469.27 470 1390

C22H28FN3O2 385.22 386 1391

C29H38FN3O4 511.29 512 1392

C26H36FN3O3 457.27 458 1393

C25H34FN3O3 443.26 444 1394

C27H36FN3O3 469.27 470 1395

C26H34FN3O3 455.26 456 1396

C28H38FN3O3 483.29 484 1397

C26H36FN3O3 457.27 458 1398

C26H34FN3O4 471.25 472 1399

C28H38FN3O4 499.29 500 1400

C27H38FN3O3 471.29 472 1401

C28H40FN3O3 485.30 486 1402

C27H36FN3O4 485.27 486 1403

C27H36FN3O3 469.27 470

TABLE 11 Mono- isotopic Ex. Molecular molecular No. Structure formula wt. M + H⁺ 1404

C22H30N4O2 382.24 383 1405

C24H31ClN4O 426.22 427 1406

C23H32N4O2 396.25 397 1407

C25H27FN4O 418.22 410 1408

C23H32N4O2 396.25 397 1409

C22H30N4O2 382.24 383 1410

C23H25N5O2 403.20 404 1411

C24H33N3O2 395.26 396 1412

C23H31N3O2(S)-Konfiguration 381.24 382 1413

C23H31N3O2 381.24 382 1414

C23H30FN3O2 399.23 400 1415

C24H32FN3O2 413.25 414 1416

C24H32N4O 392.26 393 1417

C24H32FN3O2 413.25 414 1418

C24H32FN3O2(S)-configuration 413.25 414 1419

C25H34FN3O2 427.26 428 1420

C26H36FN3O2 441.28 442 1421

C26H36FN3O2 441.28 442 1422

C27H36FN3O2 453.28 454 1423

C27H38FN3O3 471.29 472

TABLE 12 Mono- isotopic Ex. Molecular molecular No. Structure formula wt. M + H⁺ 1424

C27H35N3O2 433.27 434 1425

C28H39N3O4 481.29 482 1426

C27H38N4O4 482.29 483 1427

C24H32N4O3 424.25 425 1428

C24H33N3O2 395.26 396 1429

C24H31N3O3 409.24 410 1430

C29H33FN4O3 504.25 505 1431

C27H38N4O4 482.29 483 1432

C30H43N3O5 525.32 526 1433

C25H33N3O3 423.25 424 1434

C29H41N3O5 511.30 512 1435

C26H28FN3O 417.22 418 1436

C27H30FN3O 431.24 432 1437

C28H38FN3O4 499.29 500 1438

C28H38FN3O4 499.29 500 1439

C28H38FN3O4(S)-Konfiguration 499.29 500 1440

C25H32N4O2 420.25 421 1441

C24H32C1N3O2 429.22 430 1442

C29H40FN3O4 513.30 514 1443

C30H42FN3O4 527.32 528

TABLE 13 Mono- isotopic Ex. Molecular molecular No. Structure formula wt. M + H⁺ 1444

C23H30N4O 378.24 379 1445

C23H30N4O 378.24 379 1446

C21H28N4O2 368.22 369 1447

C27H38N4O 434.30 435 1448

C26H36N4O 420.29 421 1449

C29H42N4O 462.34 463 1450

C28H38N4O 446.30 447 1451

C24H32N4O 392.26 393 1452

C26H36N4O 420.29 421 1453

C26H32N4O 416.26 417 1454

C23H31N3O2 381.24 382 1455

C24H31N3O 377.25 378 1456

C22H29N3O2 367.23 368 1457

C22H21FN4O 376.17 377 1458

C20H26N4O2 354.21 355 1459

C23H24N4O2 388.19 389 1460

C22H27ClN4O 398.19 399 1461

C22H30N4O2 382.24 383 1462

C21H21N5O2 375.17 376 1463

C22H27F2N3O2 403.21 404 1464

C22H28FN3O2 385.22 386 1465

C22H28ClN3O2 401.19 402 1466

C23H31N3O2 381.24 382 1467

C23H28F3N3O2 435.21 436 1468

C23H28F3N3O2 435.21 436 1469

C22H27F2N3O2 403.21 404 1470

C22H27ClFN3O2 419.18 420 1471

C23H28N4O2 392.22 393 1472

C23H27C1N4O2 426.18 427 1473

C22H28BrN3O2 445.14 446 1474

C26H31N3O2 417.24 418 1475

C22H27F2N3O2 403.21 404 1476

C22H28BrN3O2 445.14 446 1477

C23H30ClN3O2 415.20 416 1478

C21H27ClN4O2 402.18 403 1479

C22H30N4O2 382.24 383 1480

C22H30N4O2 382.24 383 1481

C22H30N4O2 382.24 383 1482

C24H25FN4O 404.20 405 1483

C22H29N3O3 383.22 384 1484

C20H26N4O2 354.21 355 1485

C22H28FN3O2 385.22 386 1486

C22H29N3O2 367.23 368 1487

C22H28N4O 364.23 365 1488

C25H35N3O3 425.27 426 1489

C24H33N3O3 411.25 412 1490

C22H29N5O2 395.23 396 1491

C23H25N5O2 403.20 404 1492

C23H25N5O2 403.20 404 1493

C20H22N6O 362.19 363 1494

C25H25N5O2 427.20 428 1495

C23H25N3O2 375.20 376 1496

C19H21N5O2 351.17 352 1497

C20H22N4OS2 398.12 399 1498

C21H23N5O 361.19 362 1499

C20H22N6O 362.19 363 1500

C22H28FN3O2 385.22 386 1501

C23H29FN4O2 412.23 413 1502

C22H34FN3O2 391.26 392 1503

C23H30FN3O2 399.23 400 1504

C22H28FN5O2 413.22 414 1505

C23H24FN5O2 421.19 422 1506

C23H22F3N3O2 429.17 430 1507

C24H28N4O2 404.22 405 1508

C28H33N3O2 443.26 444 1509

C24H24N4O2 400.19 401 1510

C24H26N4O3 418.20 419 1511

C23H30FN3O2 399.23 400 1512

C22H27FN4O4 430.20 431 1513

C22H29FN4O2 400.23 401 1514

C24H26N4O3 418.20 419 1515

C23H30FN3O2 399.23 400 1516

C24H29FN4O 408.23 409 1517

C25H26FN3O2 419.20 420 1518

C25H26FN3O2 419.20 420 1519

C24H26FN3O2S 439.17 440 1520

C24H30FN3O 395.24 396 1521

C25H32FN3O 409.25 410 1522

C26H27F2N3O 435.21 436 1523

C22H21ClFN3O2 413.13 414 1524

C22H22FN3O2 379.17 380 1525

C23H25N3O3 391.19 392 1526

C23H25N3O3 391.19 392 1527

C22H22FN3O2 379.17 380 1528

C23H25N3O2S 407.17 408 1529

C23H25N3O2 375.20 376 1530

C24H27N3O3 405.20 406 1531

C23H30FN3O2 399.23 400 1532

C25H31ClFN3O 443.21 444 1533

C24H25ClFN3O3 457.16 458 1534

C24H30FN3O2 411.23 412 1535

C24H27N3O3 405.20 406 1536

C23H22N4O2 386.17 387 1537

C24H25N3O3 403.19 404 1538

C24H27N3O4 421.20 422 1539

C24H25N3O3 403.19 404 1540

C24H25FN4O4 452.19 453 1541

C23H3OFN3O2 399.23 400 1542

C25H26FN3O 403.21 404 1543

C26H28FN3O2 433.22 434 1544

C28H29FN4O2 472.23 473 1545

C26H28FN3O 417.22 418 1546

C24H32FN3O2 413.25 414 1547

C22H18F5N3O2 451.13 452 1548

C24H25N3O3 403.19 404 1549

C22H21F2N3O2 397.16 398 1550

C22H21F2N3O2 397.16 398 1551

C22H21F2N3O2 397.16 398 1552

C23H23N3O4 405.17 406 1553

C28H26FN3O2 455.20 456 1554

C26H31N3O3 433.24 434 1555

C25H25F2N3O 421.20 422 1556

NC23H25N3O2S 407.17 408 1557

C24H27N3O2S 421.18 422 1558

C24H27N3O2 389.21 390 1559

C24H27N3O2 389.21 390 1560

C23H22F3N3O3 445.16 446 1561

C25H29N3O2 403.23 404 1562

C25H29N3O2 403.23 404 1563

C21H22N4O2 362.17 363 1564

C22H21F2N3O2 397.16 398 1565

C22H24N4O3 392.18 393 1566

C23H25N3O4S 439.16 440 1567

C22H21F2N3O2 397.16 398 1568

C23H22F3N3O3 445.16 446 1569

C23H24FN3O2 393.18 394 1570

C20H21N5O2 363.17 364 1571

C21H21FN4O2 380.17 381 1572

C23H30FN3O2 399.23 400 1573

C22H22N4O3S 422.14 423 1574

C23H25N3O2S 407.17 408 1575

C23H25N3O2S 407.17 408 1576

C23H25N3OS2 423.14 424 1577

C24H27N3O2S 421.18 422 1578

C24H27N3O2S 421.18 422 1579

C23H22N4OS 402.15 403 1580

C24H27N3O3S 437.18 438 1581

C24H25N3O2S 419.17 420 1582

C24H25N3O2S 419.17 420 1583

C23H23N3O3S 421.15 422 1584

C23H25N3OS2 423.14 424 1585

C24H27N3OS2 437.16 438 1586

C24H27N3OS 405.19 406 1587

C24H27N3OS 405.19 406 1588

C23H22F3N3O2S 461.14 462 1589

C25H29N3OS 419.20 420 1590

C25H29N3OS 419.20 420 1591

C24H25N3O3S 435.16 436 1592

C22H24N4O2S 408.16 409 1593

C23H22F3N302S 461.14 462 1594

C24H26N4O2S 434.18 435 1595

C21H24N4O2S 396.16 397 1596

C21H21FN4OS 396.14 397 1597

C25H27N3O3S 449.18 450 1598

C28H33N3OS 459.23 460 1599

C24H26N4O2S 434.18 435 1600

C25H28N4O2S 448.19 449 1601

C25H28N4O2S 448.19 449 1602

C24H28N4OS 420.20 421 1603

C24H26N4O2S 434.18 435 1604

C24H25N3O2S 419.17 420 1605

C20H21N3OS2 383.11 384 1606

C26H28FN3O2 433.22 434 1607

C26H27ClFN3O2 467.18 468 1608

C21H21FN4OS 396.14 397 1609

C24H32FN3O2 413.25 414 1610

C25H34FN3O2 427.26 428 1611

C25H34FN3O2 427.26 428 1612

C26H34FN3O2 439.26 440 1613

C25H25N3OS 415.17 416 1614

C23H22N4OS 402.15 403 1615

C24H22FN3OS 419.15 420 1616

C23H22N4OS 402.15 403 1617

C21H27N5O3 397.21 398 1618

C25H28N4O2 416.22 417

Synthesis of Pyrrolidinylanilines Required as Intermediates [1-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine

Method C-a

3-Dimethylaminopyrrolidine (0.34 g) was slowly added to a solution of 2-chloro-1 fluoro-4-nitrobenzene (0.52 g) in DMF (5 ml). After 1 hour, ethyl acetate (30 ml) was added to the reaction mixture, and it was extracted with 10% hydrochloric acid (2×20 ml). The aqueous phase was washed with ethyl acetate (2×20 ml), adjusted to pH>10 with 10% ammonia and extracted with ethyl acetate. The yellow solution was dried with sodium sulfate, filtered and concentrated in a rotary evaporator. The residue was then dissolved in dichloromethane (50 ml), zinc (10 g) was added, and glacial acetic acid (5 ml) was slowly added dropwise while cooling in ice. The suspension was stirred for 15 minutes, filtered, washed with 10% ammonia (2×20 ml) and concentrated. This resulted in the product with the molecular weight of 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),

5-Amino-2-(3-dimethylaminopyrrolidin-1-yl)benzonitrile

Dimethylaminopyrrolidine was treated with 2-fluoro-5-nitrobenzonitrile and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 230.32 (C13H18N4); MS (ESI): 231 (M+H+),

[1-(4-Amino-3-chlorophenyl)pyrrolidin-3-yl]dimethylamine

Dimethylaminopyrrolidine was treated with 3-chloro-1-fluoro-4-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),

[1-(4-Amino-3-methylphenyl)pyrrolidin-3-yl]dimethylamine

Dimethylaminopyrrolidine was treated with 4-fluoro-2-methyl-1-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 219.33 (C13H21N3); MS (ESI): 220 (M+H+).

tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

Method C-b

tert-Butyl (R)-(+)-pyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension of 3,4-difluoronitrobenzene (1.59 g) and potassium carbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (10 ml), and sodium hydride (0.48 g) was added. After 15 minutes, methyl iodide (1.41 g) was then added while cooling in ice. After 30 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).

tert-Butyl (S)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was obtained analogously.

tert-Butyl (R)-[1-(2-fluoro-4-isopropylaminophenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with acetone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 351.47 (C19H30FN3O2); MS (ESI): 352 (M+H+).

tert-Butyl (R)-[1-(2-Fluoro-4-cyclobutylaminophenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with cyclobutanone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+).

tert-Butyl (R)-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate was treated as described for method B. This resulted in the product with the molecular weight of 323.41 (C17H26FN3O2); MS (ESI): 324 (M+H+).

tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}-methylcarbamate

tert-Butyl (R)-(+)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate (0.93 g) was added to a solution of N-(benzyloxycarbonyloxy)succinimide (2.49 g) in dichloromethane (30 ml). After 12 hours, the mixture was washed with water (2×30 ml), dried sodium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile. The product obtained in this way was dissolved in DMF (10 ml), and sodium hydride (0.24 g) was added. After 15 minutes, methyl iodide (0.71 g) was added while cooling in ice. After 15 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×30 ml), dried sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 457.55 (C25H32FN3O4); MS (ESI): 458 (M+H+).

(R)-[1-(2-Fluoro-4-methylaminophenyl)pyrrolidin-3-yl]dimethylamine

(R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was methylated by method M. Finally, hydrogenation was carried out by method B. This resulted in the product with the molecular weight of 237.32 (C13H20FN3); MS (ESI): 238 (M+H+).

Dimethyl-[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine can be prepared analogously.

2-Dimethylamino-N-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]-N-methylacetamide

(R)-{1-[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3-yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was reacted with N,N-dimethylglycine by method E. Finally, hydrogenation was carried out by method B. This resulted in the product with the molecular weight of 308.40 (C16H25FN4O); MS (ESI): 309 (M+H+).

tert-Butyl (R)-[1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

2,4-Difluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate, methylated and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).

tert-Butyl [1-(4-aminonaphthalen-1-yl)pyrrolidin-3-yl]methylcarbamate

Method C-c

tert-Butyl methylpyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension of 4-fluoro-1-nitronaphthalene (1.91 g) and potassium carbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3×50 ml) in a separating funnel, dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 341.46 (C20H27N3O2); MS (ESI): 342 (M+H+).

tert-Butyl [1-(4-amino-3-bromophenyl)pyrrolidin-3-yl]methylcarbamate

2-Bromo-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 370.29 (C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+).

Tert-butyl [1-(4-amino-3-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

2-Cyano-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 316.41 (C17H24N4O2); MS (ESI): 317 (M+H+).

tert-Butyl [1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-6-fluoro-3-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 326.83 (C15H23ClN4O2); MS (ESI): 326 (M+H+), 327 (M+H+).

tert-Butyl [1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

2,3,4-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

tert-Butyl [1-(4-amino-2-bromophenyl)pyrrolidin-3-yl]methylcarbamate

3-Bromo-4-fluoro-1-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 370.29 (C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+).

tert-Butyl [1-(4-amino-2,6-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

3,4,5-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

tert-Butyl (R)-[1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]carbamate

(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 307.40 (C16H25N3O3); MS (ESI): 308 (M+H+).

tert-Butyl [1-(4-amino-2-chlorophenyl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-1-fluoro-4-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 311.81 (C15H22ClN3O2); MS (ESI): 311 (M+H+), 312 (M+H+).

tert-Butyl [1-(4-amino-2,5-difluorophenyl)pyrrolidin-3-yl]methylcarbamate

3,4,6-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).

tert-Butyl [1-(4-amino-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate

tert-Butyl 4-fluoro-3-methylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

tert-Butyl [1-(4-amino-3-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate

4-Fluoro-2-trifluoromethyinitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).

tert-Butyl [1-(4-amino-2-chloro-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate

2,4-Difluoro-3-chloronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 329.80 (C15H21ClN3O2); MS (ESI): 329 (M+H+), 330 (M+H+).

tert-Butyl [1-(4-amino-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

3-Cyano-4-fluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 302.38 (C16H22N4O2); MS (ESI): 303 (M+H+).

tert-Butyl [1-(4-amino-5-chloro-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate

1-Chloro-5-fluoro-4-methyl-2-nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 325.84 (C16H24ClN3O2); MS (ESI): 325 (M+H+), 326 (M+H+).

tert-Butyl (R)-[1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).

tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).

tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate

4-Fluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

tert-Butyl [1-(4-amino-2-trifluoromethylphenyl)pyrrolidin-3-yl]methylcarbamate

4-Fluoro-3-trifluoromethylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).

tert-Butyl [1-(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-4-methyl-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).

tert-Butyl [1-(5-amino-3-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-3-methyl-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).

tert-Butyl [1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]methylcarbamate

(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 321.42 (C17H27N3O3); MS (ESI): 322 (M+H+).

tert-Butyl [1-(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate

2-Chloro-6-fluoro-3-nitrobenzonitrile was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 350.5 (C17H23ClN4O2); MS (ESI): 350 (M+H+), 351 (M+H+).

tert-Butyl [1-(4-amino-3-methylphenyl)pyrrolidin-3-yl]methylcarbamate

4-Fluoro-2-methylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).

tert-Butyl [1-(5-aminopyridin-2-yl)pyrrolidin-3-yl]carbamate

2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).

5-(3-Dimethylaminopyrrolidin-1-yl)pyridin-2-ylamine

A suspension of 5-bromo-2-nitropyridine (2 g), 3-(dimethylamino)pyrrolidine (1.14 g), (R)-(+)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.5 g), palladium(II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 ml) was heated at 100° C. for 3 hours. Cooling to room temperature was followed by extraction with 1N hydrochloric acid (2×100 ml). The aqueous phase was adjusted to pH>10 with ammonia, extracted with ethyl acetate (2×100 ml), dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 206.29 (C11H18FN4); MS (ESI): 207 (M+H+).

N-[1-(4-Aminophenyl)-4-hydroxypyrrolidin-3-yl]-N-methylacetamide

trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+).

trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide

tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1-carboxylate (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and acetic anhydride (0.567 g). After 3 hours, volatile fractions were removed under high vacuum. The residue was treated by method G. This resulted in the product with the molecular weight of 158.20 (C7H14N2O2); MS (ESI): 159 (M+H+).

trans-1-(4-Aminophenyl)-4-dimethylaminopyrrolidin-3-ol

tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was stirred with dimethylamine (40% aq., 10 ml) for 12 hours. The mixture was concentrated and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was treated by method G. The resulting amine was reacted with 4-fluoronitrobenzene by method C. The resulting nitro compound was hydrogenated by method B. This resulted in the product with the molecular weight of 221 (C12H19N3O); MS (ESI): 222 (M+H+).

[1-(4-Aminophenyl)-4-methoxypyrrolidin-3-yl]dimethylamine

An alternative possibility is for the nitro compound prepared in the preceding method to be alkylated with methyl iodide by method F and then hydrogenated by method B. This resulted in the product with the molecular weight of 235 (C13H21N3O); MS (ESI): 236 (M+H+).

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine

Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 205.31 (C12H19N3); MS (ESI): 206 (M+H+).

1-(4-Aminophenyl)-3-dimethylaminopyrrolidin-2-one

Trisodium phosphate (3.56 g) was added to a solution of 4-nitroaniline (5.0 g) in acetonitrile (30 ml) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (11 g) was added. After one hour, a solution of sodium hydroxide (3.2 g) in water (10 ml) was added, and the mixture was vigorously stirred at room temperature. After 6 hours, the same amount of sodium hydroxide solution was again added, and the mixture was left to stand overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product (0.5 g) was heated with dimethylamine (160 mg) in toluene (20 ml) at 80° C. for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).

1-(4-Aminophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one was obtained in an analogous manner.

4-[3-(7-Azabicyclo[2.2.1 ]hept-7-yl)pyrrolidin-1-yl]phenylamine

1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in THF (10 ml) was mixed with borane-THF complex (1M in THF, 0.83 ml) and boiled under reflux for 3 hours. After the reaction was complete, the mixture was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4N). Extraction in ethyl acetate, drying and concentration of the organic phase afforded a crude product that was hydrogenated by method B. This resulted in the product with the molecular weight of 257.38 (C16H23N3); MS (ESI): 258 (M+H+).

(R)-1′-(4-Aminophenyl)-[1,3′]bipyrrolidinyl-2-one

tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and-ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).

1-Methylpiperidine-3-carboxylic acid [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]methylamide

tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]methylcarbamate was treated by method G and reacted with 1-methylpiperidine-3-carboxylic acid by method E. Finally, hydrogenation was also carried out by method E. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).

(R)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2-dimethylamino-N-methylacetamide was obtained in an analogous manner using N,N-dimethylglycine.

N-[(R)-1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide

N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).

N-(2-Diethylaminoethyl)-N-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide

Acetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane, mixed with 5.3 ml of triethylamine, and after addition of N,N-diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), stirred at room temperature for 30 minutes. Subsequently, (LCMS check), water (10 ml) was added to the reaction, and the mixture was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over magnesium sulfate, the solvent was removed, and the crude product was separated by chromatography on silica gel (dichloromethane/methanol 10:1). This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).

N,N-Diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]ethane-1,2-diamine

tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (7.9 g) was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 306.41 (C16H26N4O2); MS (ESI): 307 (M+H+).

tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate

tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3×50 ml) and drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).

Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide

Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was then treated by method G. This resulted in the product with the molecular weight of 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).

Synthesis of Amines Required as Intermediates Spiro[1,3-benzodioxol-2,1′-cyclopentane]-5-amine

A solution of spiro[5-nitro-1,3-benzodioxol-2,1′-cyclopentane] (8.8 g) in methanol (90 ml) was hydrogenated under 6 bar in the presence of palladium on carbon (10%, 0.1 g). After 30 minutes at room temperature, the mixture was filtered and concentrated. This resulted in the product with the molecular weight of 191.23 (C11H13NO2); MS(ESI): 192 (M+H+).

Spiro[5-nitro-1,3-benzodioxol-2,1′-cyclopentane]

A solution of spiro[1,3-benzodioxol-2,1′-cyclopentane] (8.5 g) in 20 ml of dichloromethane was added dropwise at 10° C. to 65% strength nitric acid (65 ml). After 2 hours at 5-10° C., the mixture was diluted with water, the organic phase was separated off, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water until neutral, dried over sodium sulfate, concentrated and crystallized from heptane. This resulted in the product with the molecular weight of 221.21 (C11H11NO4); MS(ESI): 222 (M+H+).

Spiro[1,3-benzodioxol-2,1′-cyclopentane]

Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (C11H12O2); MS(ESI): 177 (M+H+).

5-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol

Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated by method G. This resulted in the product with the molecular weight of 212.68 (C10H13ClN2O); MS(ESI): 213 (M+H+).

The following were obtained analogously:

-   5-Fluoro-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol -   6-Chloro-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol.

6-Cyclopentyloxypyridin-3-ylamine

A mixture of 2-hydroxy-5-nitropyridine (1.4 g), cyclopentyl bromide (1.5 g) and potassium carbonate (3 g) was heated in DMF (20 ml) at 80° C. for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). The nitro compound obtained in this way was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N2O2); MS(ESI): 179 (M+H+).

6-(4-Fluorophenyl)-3-azabicyclo[4.1.0]heptane

Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixed with trifluoroacetic acid (3 ml) at 0° C. After 20 minutes, diiodomethane (3 ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1N), the phases were separated and the organic phase was washed with water, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 191.25 (C12H14FN); MS(ESI): 192 (M+H+).

Synthesis of Carboxylic Acids Required as Intermediates 4-(4-Methylpiperidin-1-yl)benzoic acid

4-(4-Methylpiperidin1-yl)benzonitrile (1.2 g) was heated to reflux with potassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml) for 3 hours. The mixture was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitated product was filtered off with suction, dissolved in dichloromethane, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 219.29 (C13H17NO2); MS(ESI): 220 (M+H+).

4-(4-Methylpiperidin1-yl)benzonitrile

4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 180° C. for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This resulted in the product with the molecular weight of 200.29 (C13H16N2); MS(ESI): 201 (M+H+).

4-Butoxycyclohexanecarboxylic acid

Sodium hydride (2.78 g) was added to a solution of ethyl 4-hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF while cooling in ice under argon. After 12 hours, the mixture was poured onto ice (200 g), extracted with ethyl acetate (100 ml) and then washed with water (3×50 ml). The organic phase was concentrated and mixed with ethanol (50 ml) and 5N sodium hydroxide (30 ml). The solution was heated at 60° C. for 4 hours. Cooling to room temperature was followed by adjustment to pH<2 with 2N hydrochloric acid, extraction with ethyl acetate (3×50 ml), drying with magnesium sulfate, filtration and concentration. This resulted in the product with the molecular weight of 200.28 (C11H20O3); MS (ESI): 201 (M+H+).

1-Benzyl-1H-[1,2,3]triazole-4-carboxylic acid

Methyl 1-benzyl-1H-[1,2,3]triazol-4-carboxylate (217 mg) was dissolved in 4 ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution. After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitate was filtered off, taken up in 5 ml of ethyl acetate and purified by preparative HPLC. This resulted in the product with the molecular weight of 203.2 (C10H9N3O2); MS (ESI): 204 (M+H+).

Methyl 1-benzyl-1H-[1,2,3]triazole-4-carboxylate

Benzyl azide (266 mg) was dissolved together with sodium ascorbate (20 mg) and copper sulfate (5 mg) in 8 ml of the solvent mixture (tert-butanol/water 3:1), and methyl propionate (336 mg) was added. The solution was stirred at room temperature for 2 hours. A white precipitate separated out and was filtered off with suction on a frit and subsequently dried. This resulted in the product with the molecular weight of 217.23 (C11H11N3O2); MS (ESI): 218 (M+H+).

1-Biphenyl-4-yl-1H-[1,2,3]triazole-4-carboxylic acid was prepared analogously from 4-Ethynylbiphenyl and ethyl azidoacetate.

1-Butyl-1H-indole-5-carboxylic acid

Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).

3′-Acetylaminobiphenyl-4-carboxylic acid

3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g) and acetic anhydride (180 mg) and, after 14 hours, volatile fractions were removed. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 255.28 (C15H13NO3); MS (ESI): 256 (M+H+).

3′-Isobutyrylaminobiphenyl-4-carboxylic acid

3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethane with potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 283.33 (C17H17NO3); MS (ESI): 284 (M+H+).

5-Butoxypyridine-2-carboxylic acid

Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5-hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g) was added. The mixture was heated at 90° C. for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated in analogy to method B. This resulted in the product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+).

4-Methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-carboxylic acid

Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) was heated with 4-methylpiperidine (1.4 g) at 80° C. for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in analogy to method. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid

Method P-a

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester (1.7 g) dissolved in methanol (20 ml) was stirred with sodium hydroxide solution (2N, 15 ml) at room temperature for 24 hours. If conversion is incomplete, it is also possible to heat to reflux. The organic solvent was distilled off, and the mixture was acidified with hydrochloric acid. The precipitate which separated out was filtered off with suction and dried. This resulted in the product with the molecular weight of 353.42 (C20H23N3O3); MS (ESI): 354 (M+H+).

N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with terephthalic acid monomethyl ester by method E. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).

4-(Cyclopentanecarbonylmethylamino)benzoic acid

Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylic acid by method E and then hydrolyzed by method P-a. This resulted in the product with the molecular weight of 247.30 (C14H17NO3); MS (ESI): 248 (M+H+).

The following compounds were obtained analogously:

-   4-(Cyclopentanecarbonylamino)-3-methoxybenzoic acid -   2-Chloro-4-(cyclopentanecarbonylamino)benzoic acid -   2-Fluoro-4-(cyclopentanecarbonylamino)benzoic acid -   4-(Cyclopentanecarbonylamino)-3-methylbenzoic acid -   4-(Cyclopentanecarbonylamino)benzoic acid -   4-(Cyclopentanecarbonylamino)-3-trifluoromethoxybenzoic acid -   3-Chloro-4-(cyclopentanecarbonylamino)benzoic acid -   5-Chloro-4-(cyclopentanecarbonylamino)-2-methoxybenzoic acid -   4-[(Cyclohex-1-enecarbonyl)amino]benzoic acid -   4-[(Cyclopent-1-enecarbonyl)amino]benzoic acid

3-Fluoro-4-(1-methylbutoxy)benzoic Acid

A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone in 6.8 ml of dioxane was dropped dropwise into 1.36 g of NaOH, 1.6 g of bromine in 6.8 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated at 50° C. for 1 h. The excess bromide was decomposed by adding a sodium disulfite solution, and then the solution was poured into 25% strength hydrochloric acid solution and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic phases dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 226.1 (C12H15FO3); MS (ESI): 227 (M+H+).

1-[3-Fluoro-4-(1-methylbutoxy)phenyl]ethanone

0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution was stirred at room temperature for 1 hour. Then 0.312 g of 3,4-difluoroacetophenone was added, and the mixture was stirred at room temperature overnight. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting compound was reacted further without further purification.

The following compounds were obtained analogously:

-   4-Cyclobutoxy-3-fluorobenzoic acid -   3-Fluoro-4-(2-methylcyclopropylmethoxy)benzoic acid -   4-(2-Cyclopropylethoxy)-3-fluorobenzoic acid -   3-Fluoro-4-(1-methylpiperidin-3-yloxy)benzoic acid -   4-(1-Acetylpiperidin-3-yloxy)-3-fluorobenzoic acid -   3-Fluoro-4-(1-methylpyrrolidin-3-yloxy)benzoic acid -   4-(1-Acetylpyrrolidin-3-yloxy)-3-fluorobenzoic acid -   3-Fluoro-4-(1-methylpiperidin-3-ylmethoxy)benzoic acid

4-(2,4-Difluorophenoxy)benzoic Acid

0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl 4-(2,4-difluorophenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated at 110° C. for 6 hours. The THF was then removed in vacuo, and the aqueous phase was freeze dried and purified by preparative HPLC. This resulted in the product with the molecular weight of 250.04 (C13H8F2O3); MS (ESI): 251 (M+H+).

Ethyl 4-(2,4-difluorophenoxy)benzoate

0.018 g of NaH was added to a solution of 0.1 g of 2,4-difluorophenol in 0.5 ml of DMF. The reaction was stirred at room temperature for 45 minutes. Then 0.129 g of ethyl 4-fluorobenzoate in 0.5 ml of DMF was added dropwise. The reaction was heated at 110° C. overnight. After cooling concentrated in vacuo and the residue taken up in ethyl acetate/water. The ethyl acetate phase was washed three times with water, dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 278.08 (C15H12F2O3); MS (ESI): 279 (M+H+)

4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 437.19 (C25H25F2N3O2); MS (ESI): 438 (M+H+) as hydrotrifluoroacetate.

4-Butoxy-3-methoxybenzoic acid

Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane by method H and hydrolyzed by method P-a. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+).

The following compounds were prepared analogously:

-   4-Butoxy-3,5-dichlorobenzoic acid -   4-Butoxy-3-nitrobenzoic acid -   4-Butoxy-3-chlorobenzoic acid -   4-Butoxy-3,5-dimethylbenzoic acid -   4-Butoxy-2,3-dichloro-5-methoxybenzoic acid -   4-Butoxy-2,3,5,6-tetrafluorobenzoic acid -   4-Butoxy-3-fluorobenzoic acid -   3-Acetyl-4-butoxybenzoic acid -   2,4-Dibutoxybenzoic acid -   4-Butoxy-2-chlorobenzoic acid

4-Propoxymethylbenzoic Acid

Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution of propanol (0.6 g) in DMF (8 ml). After gas evolution ceased, methyl 4-bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 194.23 (C11H14O3); MS (ESI): 195 (M+H+).

The following compounds were prepared analogously:

-   4-Ethoxymethylbenzoic acid -   4-Butoxymethylbenzoic acid -   4-Isobutoxymethylbenzoic acid -   4-Phenoxymethylbenzoic acid -   4-(Pyridin-3-yloxymethyl)benzoic acid -   4-(Pyridin-2-yloxymethyl)benzoic acid -   4-Benzoimidazol-1-ylmethylbenzoic acid -   4-Indol-1-ylmethylbenzoic acid -   4-Phenylsulfanylmethylbenzoic acid -   4-(Pyrimidin-2-ylsulfanylmethyl)benzoic acid -   4-(Pyridin-2-ylsulfanylmethyl)benzoic acid -   4-(2-Cyanophenoxymethyl)benzoic acid -   4-(2-Chlorophenoxymethyl)benzoic acid -   4-Cyclobutoxymethylbenzoic acid -   4-Cyclopentyloxymethylbenzoic acid -   4-Cyclohexyloxymethylbenzoic acid -   4-sec-Butoxymethylbenzoic acid -   4-Pentoxymethylbenzoic acid

4-(3-Oxo-3a,4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl)benzoic acid

A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2-oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) in ethanol (12 ml) was boiled under reflux for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 244.25 (C13H12N2O3); MS (ESI): 245 (M+H+).

4-Butoxy-2-methoxybenzoic acid

4-Hydroxy-2-methoxybenzaldehyde was alkylated with 1-bromobutane by method H. The resulting aldehyde (6.4 g) in dioxane (100 ml) was mixed with sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 ml), and the solution was cooled to 10° C. A solution of sodium chlorite (3.61 g) in water (100 ml) was added in such a way that the temperature did not exceed 10° C. 15 minutes after the addition was complete, sodium sulfite (4.6 g) was added. After a further 15 minutes, the pH was adjusted to 2 with hydrochloric acid and the dioxane was removed in a rotary evaporator. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 224.26 (C12H16O4); MS (ESI): 225 (M+H+). 4-Butoxy-5-chloro-2-methoxybenzoic acid was obtained as by-product.

4-(1-Propoxyethyl)benzoic acid

Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was mixed with propyl iodide (3.8 g), and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture was stirred for 1 hour and then water was cautiously added. It was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 208.26 (C12H16O3); MS (ESI): 209 (M+H+). 

1. A compound of the formula I

wherein R1, R2 are each independently H, (C₁-C₈)-alkyl, -(CR78R79)_(o)-R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, aryloxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl, CO—(C₂-C₈)-alkenyl, CO—(C₂-C₈)-alkynyl, COCH═CH(R13), COCC(R14), CO—(C₁-C₄)-alkyl-S(O)_(p)—(C₁-C₄)-alkyl, CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(r)CON(R21)(R22) or CO(C(R23)(R24))_(s)O(R25); or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1, 2, 3 or 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃; wherein o is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1 or 2 q, r, s are each independently 0, 1, 2, 3 or 4; R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl; R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system which optionally contains 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R12 is OH, O—(C₁-C₆)-alkyl, O(C₀-C₈)-alkylene-aryl, CN, S—(C₁-C₆)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u)(R41) or COOH; t is 0, 1, 2, 3, 4, 5 or 6; u is 0, 1 or 2; R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl; or R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains one or two additional heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl; R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring system optionally containing one or two heteroatoms from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R78, R79 are each independently H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R80, R81, R93 are each independently (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl; R82, R83 are each independently H or (C₁-C₆)-alkyl; or R82 and R83, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R3 is H or (C₁-C₆)-alkyl; R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group; n, m are each independently 0, 1 or 2; A, B, D, G are each independently N or C(R42); or said radicals A and B, or said radicals D and G are each C(R42) and, taken together, optionally form a 5- or 6 membered carbocyclic or heterocyclic radical resulting in an overall bicyclic ring system; wherein R42 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R43)(R44), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO₂(R50), CO(R51) or -(CR84R85)_(x)-O(R86); wherein R43, R44, R45, R46, R47, R49 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl; R84, R85 are each independently H or (C₁-C₈)-alkyl; R86 is H, (C₁-C₆)-alkyl or aryl; x is 1, 2, 3, 4, 5 or 6; R10 is H, (C₁-C₈)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-alkynyl; X is N(R52) or O; wherein R52 is H or (C₁-C₈)-alkyl; E is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13- or 14-membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and optionally substituted with H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65), and wherein said bivalent carbo- or heterocyclic ring structure is mono- or bicyclic; wherein R57, R58, R59, R60, R61, R63 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl; K is a bond, O, OCH₂, CH₂O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))_(V), CO, C≡C, C═C or a group of the formula -(CR90R91)_(z)- in which one or more of the -(CR90R91)- units contained in said group of the formula -(CR90R91)_(z)- is optionally replaced by Z; wherein v is 1, 2, 3 or 4 R66, R67, R68, R69, R70 are each independently H or (C₁-C₈)-alkyl; Z is O, S, N(R92), CO, SO or SO₂; R90, R91 are each independently H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, hydroxy or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, and wherein R90 and R91 may be defined the same or differently in each of said -(CR90R91)- units contained in said group of formula -(CR90R91)_(z)-; z is 2, 3, 4, 5 or 6; R92 is H or (C₁-C₈)-alkyl; R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(C₁-C₄)-alkyl, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77), SO₂CH₃ or SCF₃; wherein R71, R72, R73, R74, R75, R76, R77 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; or E, K and R11 taken together form a tricyclic system where each of the rings in said tricyclic system are, independently of one another, saturated, partially saturated or unsaturated, and wherein each ring is comprised of 3-8 ring atoms; and the N-oxides and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 of formula 1:

wherein R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, aryloxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl, CO—(C₂-C₈)-alkenyl, CO—(C₂-C₈)-alkynyl, COCH═CH(R13), COCC(R14), CO—(C₁-C₄)-alkyl-S(O)_(p)—(C₁-C₄)-alkyl, CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(r)CON(R21)(R22) or CO(C(R23)(R24))_(s)O(R25); or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1, 2, 3 or 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃; wherein o is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1 or 2 q, r, s are each independently 0, 1, 2, 3 or 4; R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl; R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system which optionally contains 1 or 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R12 is OH or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40), S(O)_(u)(R41) or COOH; t is 0, 1, 2, 3, 4, 5 or 6; u is 0, 1 or 2; R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl; or R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains one or two additional heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl; R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring system optionally containing one or two heteroatoms from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R3 is H or (C₁-C₆)-alkyl; R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group; n, m are each independently 0, 1 or 2; A, B, D, G are each independently N or C(R42); wherein R42 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF_(3,)O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R43)(R44), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO₂(R50) or CO(R51); wherein R43, R44, R45, R46, R47, R49 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl; R10 is H, (C₁-C₈)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-alkynyl; X is N(R52) or O; wherein R52 is H or (C₁-C₈)-alkyl; E is a 3, 4, 5, 6, 7 or 8-membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and optionally substituted with H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65), and wherein said bivalent carbo- or heterocyclic ring structure is mono- or bicyclic; wherein R57, R58, R59, R60, R61, R63 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl; K is a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))_(v), CO or C≡C; wherein v is 1, 2, 3 or 4 R66, R67, R68, R69, R70 are each independently H or (C₁-C₈)-alkyl; R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl or a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃; wherein R71, R72, R73, R74, R75, R76, R77 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from the nitrogen atom, optionally contain one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; or E, K and R11 taken together form a tricyclic system where each of the rings in said tricyclic system are, independently of one another, saturated, partially saturated or unsaturated, and wherein each ring is comprised of 3-8 ring atoms; and the N-oxides and pharmaceutically acceptable salts thereof.
 3. The compound of claim 2 wherein R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CH₂)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, COCH═CH(R13), COCC(R14), CO—(C₁-C₄)-alkyl-S(O)_(p)—(C₁-C₄)-alkyl, CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(r)CON(R21)(R22) or CO(C(R23)(R24))_(s)O(R25); or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally contains 1 or 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃; o 0, 1, 2, 3 or 4; p 0, 1 or 2; q, r, s are each independently 0, 1, 2 or 3; R13, R14 are each independently a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally containing a further heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl; R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system which optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur and is optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R12 is OH or a 3-, 4-, 5-, 6, 7-, 8-, 9-, 10-, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40) or S(O)_(u)(R41); t 0, 1, 2, 3 or 4; u 0, 1 or 2; R34, R35, R37, R38 are each independently H or (C₁-C₈)-alkyl; or R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5- or 6-membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system wherein said aromatic ring system optionally contains a further heteroatom selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl; R41 is (C₁-C₆)-alkyl or a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring system optionally containing one or two heteroatoms selected from the group of nitrogen, oxygen and sulfur, and optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R3 is H or (C₁-C₆)-alkyl; R4, R5 are each independently H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl or O—CO(C₁-C₆)-alkyl; R6, R7, R8, R9 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R6 and R7, and R8 and R9, optionally form, independently of one another, an oxo group; n, m are each independently 0, 1 or 2; A, B, D, G are each independently N or C(R42); R42 is H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, (C₀-C₂)-alkylene-aryl, O—(C₀-C₂)-alkylene-aryl, N(R43)(R44), SO₂—CH₃, COO—(C₁-C₆)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO₂(R50) or CO(R51); R43, R44, R45, R46, R47, R49 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl; R10 is H or (C₁-C₈)-alkyl; X is N(R52) or O; R52 is H or (C₁-C₈)-alkyl; E is a 3-, 4-, 5-, 6-, 7- or 8 membered bivalent carbo- or heterocyclic ring structure with 0, 1, 2, 3, or 4 heteroatoms from the group of N, O and S, and optionally substituted with H, F, Cl, CF₃, NO₂, OH, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R57)(R58), SO₂—CH₃, COO—(C₁-C₆)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65), and wherein said bivalent carbo-or heterocyclic ring is mono- or bicyclic; R57, R58, R59, R60, R61, R63 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R57 and R58, and R59 and R60, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one further heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl; K is a bond, O, CH₂O, N(R66), (C(R69)(R70))_(v) or C≡C; v is 1 or 2; R66, R67, R68, R69, R70 are each independently H or (C₁-C₈)-alkyl; R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring, optionally containing 1, 2, 3 or 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃; R71, R72, R73, R74, R75, R76, R77 are each independently H or (C₁-C₈)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur.
 4. The compound of claim 3, wherein A, B, D, G are each independently N or C(R42), and the total number of nitrogen atoms in said ring is 0-2.
 5. The compound of claim 4, wherein n is 1 and m is 1 or
 2. 6. The compound of claim 1 wherein R1, R2 are each independently H, (C₁-C₈)-alkyl, —(CR78R79)_(o)-R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO-aryloxy-(C₁-C₄)-alkyl, COCH═CH(R13), COCC(R14), CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(r)CON(R21)(R22), CO(C(R23)(R24))_(s)O(R25); or R1 and R2, taken together with the nitrogen atom to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered mono-, bi- or spirocyclic ring which, apart from said nitrogen atom of attachment, optionally comprises one or two additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, and is optionally substituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C₁-C₆)-alkyl, N(R31)(R32) or SO₂CH₃; o is 0, 1, 2, 3, 4, 5 or 6; q, r are independently of one another 1, 2 or 3; s is 0, 1, 2, 3 or 4; R13, R14 are each independently an aryl ring optionally comprising one nitrogen atom; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are each independently H or (C₁-C₆)-alkyl; R18 is H, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl or CO(R33); or substituent pairs R17 and R18, R21 and R22, R27 and R28, R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains 1 further heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R33 is a 5-, 6-, 7-, 8-, 9- or 10 membered aromatic ring system optionally comprising one additional heteroatom selected from the group of nitrogen, oxygen and sulfur and optionally substituted by F, Cl, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R12 is OH, O—(C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, CN, S—(C₁-C₆)-alkyl, COO(R80), CON(R81)(R82), or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10, 11- or 12 membered mono-, bi- or spirocyclic ring which optionally contains one or more heteroatoms from the group of N, O and S, and is optionally substituted by F, Cl, Br, OH, CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35), COCH═CH(R36), (C(R37)(R38))_(t)(R39), CO(C(R37)(R38))_(t)(R39), CO(C₁-C₆)-alkyl, COCOO(C₁-C₆)-alkyl, COO(R40) or S(O)_(u)(R41); t is 0, 1, 2, 3, 4, 5 or 6; u is 0, 1 or 2; R34, R35, R37, R38 are independently of one another H or (C₁-C₈)-alkyl; or substituent pair R34 and R35, taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur, and is optionally substituted by 1 or 2 oxo groups; R36, R39 are each independently (C₃-C₈)-cycloalkyl or a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl; R40 is H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl or (C₀-C₈)-alkylene-aryl; R41 is (C₁-C₆)-alkyl or a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl; R78, R79 are independently of one another H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R80, R81 are independently of one another H or (C₁-C₈)-alkyl; R3 is H or (C₁-C₆)-alkyl; R4, R5 are independently of one another H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; R6, R7, R8, R9 is H; or substituent pairs R6 and R7, and R8 and R9, independently of one another, optionally form oxo; n is 1; m is 1 or 2; A, B, D, G are independently of one another N or C(R42); or the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system; R42 is H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R43)(R44), SO₂—CH₃, CON(R45)(R46), N(R47)CO(R48), CO(R51) or —(CR84R85)_(x)—O(R86); R43, R44, R45, R46, R47 are independently of one another H, (C₁-C₈)-alkyl; or substituent pairs R43 and R44, and R45 and R46, independently of one another, taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contain one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R48, R50, R51 are each independently H, (C₁-C₈)-alkyl or aryl; R84, R85 are H; R86 is H or (C₁-C₆)-alkyl; x is 0, 1 or 2; R10 is H or (C₁-C₈)-alkyl; X is N(R52) or a bond; R52 is H or (C₁-C₈)-alkyl; E is a 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, O and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R57)(R58), SO₂—CH₃, N(R61)CO(R62), N(R63)SO₂(R64) or CO(R65) and wherein said carbo- or heterocyclic ring structure may be mono- or bicyclic; R57, R58, R61, R63 are each independently H or (C₁-C₈)-alkyl; R62, R64, R65 are each independently H, (C₁-C₈)-alkyl or aryl; K is a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))_(v), CO, C═C, C≡C, SCH₂ or SO₂CH₂; v is 1, 2, 3 or 4; R66, R67, R68, R69, R70 are independently of one another H or (C₁-C₈)-alkyl; R11 is H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C₁-C₆)-alkyl, N(R76)(R77) or SO₂CH₃; R71, R72, R73, R74, R75, R76, R77 are independently of one another H or (C₁-C₈)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally contains an additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; or the N-oxides and the pharmaceutically acceptable salts thereof.
 7. The compound of claim 6 having the formula Ia

wherein R1, R2 are independently of one another H, (C₁-C₈)-alkyl, —(CR78R79)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32) or SO₂CH₃; where R¹ and R² are not both CO(R26); o is 0, 1, 2, 3 or 4; q is 1, 2 or 3; s 0, 1 or 2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 are independently of one another H or (C₁-C₆)-alkyl; or substituent pairs R17 and R18, R27 and R28, and R31 and R32, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring which, apart from said nitrogen atom of attachment, optionally comprises one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; R12 is OH, O—(C₁-C₆)-alkyl, O—(C₀-C₂)-alkylene-aryl, CN, S—(C₁-C₆)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 heteroatoms selected from the group of N, O and S, and optionally substituted by F, OH, CF₃, CN, oxo, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35), COO(R40) or CO(C₁-C₆)-alkyl; R34, R35 are independently of one another H or (C₁-C₄)-alkyl; R40 is H, (C₁-C₆)-alkyl or (C₀-C₂)-alkylene-aryl; R78, R79 are each independently H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH or (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R42, R42′ are each independently H, F, Cl, Br, CF₃, CN or (C₁-C₆)-alkyl; R10 is H or (C₁-C₈)-alkyl; X is N(R52); R52 is H or (C₁-C₈)-alkyl; E is a 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, O and S, and optionally substituted by H, F, Cl, Br, CF₃, OH, CN, OCF₃, NO₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃ or CO(R65); R65 is H or (C₁-C₈)-alkyl; K is a bond, O, OCH₂, CH₂O, S, SO₂, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))_(v), CO, C≡C, SCH₂ or SO₂CH₂; v is 1, 2 or 3, R66, R67, R68, R69, R70 are each independently H or (C₁-C₈)-alkyl; R11 is (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring optionally comprising 1 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, and optionally substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R71), hydroxy, N(R75)CO(C₁-C₆)-alkyl, or SO₂CH₃; R71, R72, R73, R74, R75, R76, R77 is each independently H or (C₁-C₈)-alkyl; or substituent pairs R72 and R73, and R76 and R77, independently of one another and taken together with the nitrogen atom to which they are attached, optionally form a 5 or 6 membered ring which, apart from said nitrogen atom of attachment, optionally contains one additional heteroatom component selected from the group of N—(C₁-C₆)-alkyl, oxygen and sulfur; or the N-oxides or pharmaceutically acceptable salts thereof.
 8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. The pharmaceutical composition of claim 8 further comprising one or more anorectic active ingredients.
 10. A method of treating obesity comprising administering to a patient in need thereof a compound of claim
 1. 11. A method of treating obesity comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.
 12. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim
 1. 13. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1 in combination with at least one further anorectic active ingredient.
 14. A method of reducing weight in mammals comprising administering to a patient in need thereof a compound of claim
 1. 